Marinesco-Sjögren Syndrome

Recessive cerebellar ataxia with cerebellar atrophy, early-onset cataracts, vacuolar myopathy and variable intellectual disability, caused by loss of function of SIL1, a co-chaperone of BiP in the endoplasmic reticulum; with the differential diagnosis of the "MSS-like" syndromes, in particular congenital cataracts, facial dysmorphism and neuropathy syndrome (CCFDN) related to CTDP1.

Literature and regulatory information updated: 26 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Marinesco-Sjögren syndrome (MSS) is a multisystem autosomal recessive disorder defined by the association of cerebellar ataxia with cerebellar atrophy, dysarthria and nystagmus, early-onset cataracts (not necessarily congenital), and myopathy with muscle weakness and hypotonia, frequently accompanied by psychomotor delay, hypergonadotrophic hypogonadism, short stature and skeletal anomalies [1]. Life expectancy appears to be near normal, although many adults have severe motor disability [1]. The molecular basis is biallelic loss of function of SIL1, which encodes a nucleotide exchange factor (NEF) for the endoplasmic reticulum (ER) chaperone BiP [16, 17]. Saudubray classifies MSS among the disorders of cellular trafficking with ataxia, describing it as spinocerebellar ataxia with cataract and intellectual disability [18, 19].

The clinical scope of an MSS diagnosis is broader than its molecular scope. About 40% of people with characteristic findings have no identifiable pathogenic variants in SIL1 [1], and some of the families published as MSS before 2005 had other disorders, chiefly CCFDN in the Roma population, cerebrotendinous xanthomatosis without xanthomas and GBA2-related disease [3, 20, 21]. This article covers SIL1-related MSS as the principal entity and develops, in dedicated subsections, the differential diagnosis with the "MSS-like" syndromes, with detail on CCFDN. The remaining early-onset ataxias and congenital cataracts are included in the differential diagnosis.

1.2. Founding descriptions and eponym

The first compatible description is attributed to Ernst Emil Moravcsik, who in 1904 described three siblings with cataracts, ocular abnormalities, neurological symptoms, short stature, spinal curvature and delayed puberty; Rodrigues and colleagues, in a Brazilian historical article from 2024, propose that his name be included in the eponym [22]. Georges Marinesco, Stefan Draganesco and D. Vasiliu published in 1931, in Encéphale, a family with congenital cataracts and delayed somatic, neurological and psychological development, and added hypogonadism, thoracic deformity and flat feet to the picture [22, 23]. Torsten Sjögren (1896–1974), a Swedish psychiatrist and geneticist from Gothenburg, published in 1947 and 1950 three families with 16 affected individuals, recessive inheritance and frequent consanguinity, under the title of hereditary congenital spinocerebellar ataxia with congenital cataract and oligophrenia [22, 24]. Torsten Sjögren is unrelated to Henrik Sjögren of the sicca syndrome; he also described Sjögren-Larsson syndrome and contributed to the description of Spielmeyer-Sjögren disease (CLN3) [22].

In 1987, Herva and colleagues, in Oulu, described four Finnish patients from two families with infantile hypotonia as the presenting sign, ataxia, cataract and intellectual disability at preschool age, cerebellar atrophy on computed tomography and a myopathy with vacuolar degeneration, fatty proliferation and, on electron microscopy, myelin bodies and autophagic vacuoles [25]. The authors then considered the entity distinct from MSS; the later identification of the same SIL1 founder variant in the Finnish patients integrated it into MSS [16, 25].

1.3. Separation of CCFDN and molecular milestones

During the 1990s, Roma families with congenital cataracts, demyelinating neuropathy and episodes of myoglobinuria were published as "MSS with rhabdomyolysis" [2]. Tournev and colleagues described in 1999, in Bulgaria, 50 patients from 19 Roma pedigrees with congenital cataracts, microcornea, predominantly motor neuropathy, facial dysmorphism and hypogonadotrophic hypogonadism, and proposed the new entity CCFDN [26]. In 2002, Lagier-Tourenne and colleagues showed that linkage to 18qter distinguished CCFDN from MSS [27], and Merlini and colleagues demonstrated, with a lod score of 3.55 at 18qter and a conserved haplotype, that the "MSS with myoglobinuria" of the Roma families and CCFDN were genetically identical [3]. In 2003, Varon and colleagues identified the intronic CTDP1 variant responsible for CCFDN [28], and in the same year homozygosity mapping localised "pure" MSS to 5q31 [29]. At the 125th European Neuromuscular Centre (ENMC) workshop, in 2004, the exclusion of allelism between CCFDN and MSS was presented, based on analysis of CTDP1 in 19 MSS families of various origins, and two loci at 5q31 were reported: the SARA2 gene, mutated in MSS associated with chylomicron retention disease, and a second gene, then unknown, for "pure" MSS [30].

In December 2005, two groups simultaneously published in Nature Genetics the identification of SIL1. The Helsinki group (Anttonen and colleagues) described four loss-of-function variants and showed similar patterns of spatial and temporal tissue expression of Sil1 and Hspa5, proposing disruption of the SIL1–HSPA5 interaction and of protein folding as the primary pathology [16]. The Aachen group (Senderek and colleagues) described nine variants that destroy the SIL1 protein and characterised MSS as a disorder of ER dysfunction [17]. In 2017, Haugarvoll and colleagues showed that a Norwegian family published as MSS in 1977 had biallelic GBA2 variants, and Osborn and colleagues described a congenital muscular dystrophy with cataracts and intellectual disability due to INPP5K, which overlaps with MSS and the dystroglycanopathies [21, 31].

1.4. Nomenclature

OMIM maintains a single entry for MSS (248800) without numbered subtypes, and GeneReviews does not define a syndromic class of MSS types [1]. The designation "MSS-like syndrome" is used in the literature for overlapping phenotypes without a SIL1 variant, with or without an identified gene [21, 32]. The current name of CCFDN in GeneReviews follows the gene–phenotype nomenclature proposal of Biesecker and colleagues (2021), with the gene as a prefix [2].

2. Molecular Genetics and Pathophysiology

2.1. The SIL1 gene and the SIL1 protein

The SIL1 gene is located at 5q31.2 (HGNC:24624; Ensembl ENSG00000120725; UniProt Q9H173; aliases BAP, ULG5 and MSS) and the reference transcript is MANE Select NM_022464.5, which encodes the protein NP_071909.1 [4, 33]. Routine sequencing covers the 10 exons of the gene [32]. The mature protein has 461 amino acids, with an N-terminal signal sequence and a C-terminal tetrapeptide that functions as an ER retrieval signal; the Armadillo-type (ARM) helical domains, encoded mainly by exons 6 to 10, mediate binding to HSPA5 [34]. SIL1 (also called BAP, BiP-associated protein) is an ER luminal glycoprotein that acts as a nucleotide exchange factor for BiP (GRP78, encoded by HSPA5), the ER-resident chaperone of the HSP70 family: it promotes the release of ADP and the binding of ATP by BiP and, thereby, the cycle of substrate binding and release [1, 4]. BiP participates in the translocation of proteins into the ER, in their folding and in quality control, and senses and responds to cellular stress; loss of SIL1 prevents the normal BiP cycle and disrupts ER quality control and the unfolded protein response (UPR) [1, 4]. MSS therefore belongs to the group of protein processing disorders [1].

2.2. Disease mechanism

The mechanism is loss of function. Most variants are predicted to cause truncation, with non-functional protein or degradation of the transcript or protein; three splicing variants in introns 6 and 9 give rise to in-frame deletions, with misfolding or absence of functional domains, and in these patients the protein is translated and detectable by immunohistochemistry [1]. In transfected COS-1 cells, a missense variant formed aggregates in the ER, as did an artificial variant lacking the last four amino acids (the putative ER retention signal) [1]. In lymphoblasts from patients with variants of different types and positions, SIL1 levels were severely reduced, which led Krieger and colleagues to propose a relatively homogeneous phenotype [35]. In neuropathology, cerebellar atrophy reflects the loss of Purkinje cells and granule cells in all lobules except the vestibulocerebellum, with residual Purkinje cells that are vacuolated or binucleated; in the SIL1-deficient mouse, loss of function causes UPR, abnormal protein accumulation and neurodegeneration of Purkinje cells, with ataxia [34].

The reference animal model is the woozy mouse (Sil1wz), deficient in Sil1. Systematic phenotyping between 5 and 26 weeks showed progressive ataxia from week 9, better performance of females than males, atrophy of glycolytic muscles (gastrocnemius, quadriceps) but not of the soleus (oxidative) at 26 weeks, increased BiP, phosphorylated eIF2α (peIF2α), Rab11 and LC3-II in glycolytic muscles, and impaired nesting behaviour at 14 weeks [36]. Inhibition of the PERK kinase, one of the UPR branches, delayed neurodegeneration and improved motor function in this model [37]. Recent cellular studies have added complementary hypotheses, all preclinical: in patient fibroblasts, maximal mitochondrial respiration and mitochondrial ATP production are reduced, with unchanged glycolysis, increased catalase and superoxide dismutase and decreased glutathione peroxidase and reductase, without increased oxidative damage [38]; 664 transcripts are differentially expressed, about 300 related to the extracellular matrix and adhesion, with reduced matrix remodelling and disorganised collagen at the myotendinous junction and in the Achilles tendon of the woozy mouse [39]; and Sil1 silencing in cortical neurons altered 205 proteins, with reduced ACTN1 and vimentin and increased IQGAP1, disrupting actin dynamics and neuronal migration, a mechanism proposed for the intellectual disability [40]. Proteomic analysis of cells from patients with MSS and with INPP5K-related disease identified dysregulation of D-3-phosphoglycerate dehydrogenase (PHGDH), an enzyme of L-serine synthesis, as a common molecular feature; L-serine improved the neuronal phenotype in sil1, phgdh and inpp5k zebrafish [41, 42].

2.3. Variant spectrum and normalisation

Published variants are mainly truncating (nonsense, frameshift, splicing), with some missense variants and single- or multi-exon deletions [1, 35]. Among others, a nonstop variant has been described in a consanguineous Chinese family with MSS and Dandy-Walker malformation, and a 5′ untranslated region variant in an Emirati child [1]. Known canonical splice-site variants include c.1029+1G>A and c.645+1G>A (Senderek 2005), c.645+2T>C (in compound heterozygosity with the Finnish founder variant) and c.453+5G>A [34]. The following table presents the variants with a population or illustrative role, normalised in VariantValidator (GRCh38, MANE Select transcript) and with the ClinVar classification consulted on 26 October 2026.

Three notations in the sources differ from current HGVS and were corrected by VariantValidator [33]. GeneReviews writes the Finnish founder variant as c.506_509dupAAGA; current HGVS omits the duplicated sequence. Goto and colleagues write p.Leu313fs and p.Glu201fs, without the new amino acid or the position of the stop codon [9]. In the case of Buchignani and colleagues, the text describes the variant as an in-frame deletion p.Q426_L435del, but c.1276_1306 spans 31 nucleotides and the normalised prediction is p.(Gln426SerfsTer22), the same used in the results section of the article [47]. Some recent variants were published on a non-MANE transcript (NM_001037633.2: c.570_572del p.(Asn190del) and c.740C>T p.(Ala247Val), in compound heterozygosity in a Chinese girl) and were not converted to NM_022464.5; the authors themselves classified both as variants of uncertain significance (VUS) [49]. The variant c.1024G>A p.(Glu342Lys), in a Greek child, was reclassified as pathogenic after structural and functional studies (protein reduced in fibroblasts, partially restored by proteasome inhibition) [50].

2.4. Inheritance, penetrance and genotype-phenotype correlations

Inheritance is autosomal recessive; heterozygotes are asymptomatic [1]. No genotype-phenotype correlations have been established: among Finnish patients, all homozygous for the same founder variant, the severity of intellectual disability and myopathy varies widely, and there is variability between siblings [1]. In the Japanese survey there were no marked clinical differences between variants [9]. Ruggieri and colleagues described an apparently milder phenotype with the missense variant p.(Glu342Lys) than with p.(Arg111Ter), an observation in a single patient [50]; Aslan and colleagues suggest, from a literature review, that splicing variants are associated with severe phenotypes, but their patient with c.453+1G>T had normal cognition [34]. Krieger and colleagues showed that normal intelligence is part of the spectrum (six patients with SIL1 variants without intellectual disability) and that SIL1 variants are invariably associated with the combination of cerebellar syndrome and chronic myopathy [35].

2.5. Allelic disorders, heterogeneity and dual pathology

No other phenotype associated with germline SIL1 variants is known [1]. The heterogeneity of MSS is locus heterogeneity: about 40% of people with characteristic findings have no SIL1 variants [1]. The detection rate depends on the entry phenotype: in a cohort of 62 patients with early-onset ataxia, cataracts and myopathy, or at least two of these, SIL1 variants were found in 60% (15/25) of those with the complete triad and in less than 3% (1/37) of those with a more variable presentation [35]. In Japan, 24 of 27 patients tested (89%) had SIL1 variants [9]. Ezgu and colleagues found variants in 8 of 15 patients (7 of 14 families) with an MSS phenotype, with no clinical feature distinguishing patients with and without SIL1 variants; in five patients, three with and two without SIL1 variants, fibroblasts had cytoplasmic inclusions similar to those in the brain of the woozy mouse, suggesting that some patients without SIL1 variants share the cellular pathogenesis [51]. The known genes of the phenocopies (CTDP1, GBA2, INPP5K, CYP27A1) are in section 6. The exome may reveal dual pathology: an Uzbek child had MSS due to homozygous SIL1 c.178G>T and congenital dysferlinopathy due to DYSF variants (NM_001130987.2: c.1000C>T p.(Arg334Trp) and c.518C>T p.(Thr173Met)), with dysferlin in 1% of fibres and ultrastructure showing signs of both disorders [48].

2.6. CTDP1 and CCFDN: molecular genetics

CTDP1 (FCP1; 18q23; HGNC:2498; transcript NM_004715.5) encodes a ubiquitous nuclear phosphatase, associated with transcription factor TFIIF through the RAP74 subunit, with an N-terminal catalytic domain, a BRCT domain and a C-terminal nuclear localisation signal; it processively removes phosphates from serines 2 and 5 of the C-terminal domain (CTD) of the largest subunit of RNA polymerase II, regulating the "CTD code", polymerase recycling, recruitment of the splicing machinery and chromatin remodelling [2, 5]. The only known pathogenic variant is the founder NM_004715.5:c.863+389C>T (historical nomenclature IVS6+389C>T), located in an antisense Alu element in intron 6 [2, 5, 52]. The substitution creates a canonical donor site that activates an upstream cryptic acceptor, with inclusion of 95 nucleotides of Alu sequence in the mRNA and a premature stop codon 17 codons downstream of exon 6 [2, 28]. Normal splicing persists at 15–35%, so the deficiency is partial; it is unknown whether complete loss is compatible with life [2]. Varon and colleagues designated CCFDN as the first pure "transcription syndrome" of RNA polymerase II [28]. The phenotype is consistent, with little variation, because all patients are homozygous for the same variant, and there are no allelic phenotypes [2]. In ClinVar the variant is classified as pathogenic or likely pathogenic by multiple submitters, without conflict [52].

3. Clinical Spectrum and Manifestations by System

3.1. Frequency of manifestations

GeneReviews estimates that at least 140 individuals with biallelic SIL1 variants had been described by 2024, in series from Finland, Germany, Italy, Turkey, Japan, Pakistan, French-speaking Canada, China, the United Arab Emirates and Morocco, among others [1]. The frequency of manifestations, calculated from the largest series (Anttonen 2005, Senderek 2005, Anttonen 2008, Riazuddin 2009, Krieger 2013, Ezgu 2014, Goto 2014), is as follows [1]:

These percentages aggregate patients of different ages and include series predating systematic molecular study; age-dependent manifestations (cataracts, hypogonadism, scoliosis) may be underestimated in patients observed only in childhood.

3.2. Japanese national survey

The study by Goto and colleagues (2014) is the only national series with data by motor milestone. A first questionnaire was sent to 5452 Japanese neurologists and paediatric neurologists (1875 responses, 34.4%) and a second to the 37 attending physicians; 36 patients were reviewed, 27 of whom had genetic testing [9]. The 24 patients with SIL1 variants (10 men and 14 women) were observed between 2 and 52 years of age (mean 20.1 ± 18.1 years) [9].

IQ/DQ: intelligence or developmental quotient. In patients with SIL1 variants, head control appeared at a mean of 7.8 ± 3.7 months and sitting at 20.0 ± 8.7 months; walking with support was acquired between 2 and 22 years (mean 5.8 ± 2.6 years) and no patient acquired independent walking; the slowly progressive, predominantly proximal weakness led to wheelchair dependence between 13 and 28 years of age (mean 17.4 ± 6.3 years) [9]. Short stature (<−2 standard deviations, SD) affected 67% (mean −3.6 SD) [9]. Patients without a SIL1 variant and those not tested had an indistinguishable clinical picture [9]. The Japanese series, dominated by the founder variant c.936dup, describes a population without independent walking; independent walking is possible in other populations and genotypes (section 10), and 9 of 14 patients with published muscle imaging walked at some stage [47].

3.3. Neuromuscular and motor system

Muscle hypotonia is usually present from infancy and causes motor delay; distal and proximal weakness is noticeable in the first decade and many patients never walk without support [1]. Weakness, detected as delayed motor milestones, appears before the cataracts [9]. Truncal ataxia, dysdiadochokinesia, nystagmus and dysarthria then become evident; motor function worsens for some years and then stabilises, at an unpredictable age and degree [1]. In young patients with muscle weakness, cerebellar ataxia may be difficult to identify [9]. Krieger and colleagues consider somatic growth retardation, skeletal anomalies and pyramidal signs to be "modestly constant" [35]. A Pakistani series of five patients described myoclonic movements and cerebral, not only cerebellar, atrophy in some patients [44].

Myopathy is a major component, and the muscle pathology of the recessive cerebellar ataxias has been reviewed taking MSS as a model [53]. In a muscle computed tomography study of nine adult Finnish patients, those with severe disability had severe, generalised muscle degeneration, with involvement of the posterior thoracic and pelvic muscles and almost all thigh muscles and, in the leg, the peroneal muscles and the posterior compartment; moderately affected patients had the same pattern to a lesser degree, and the authors concluded that the extent of the myopathy may be underestimated owing to central nervous system involvement [54]. The systematic review by Buchignani and colleagues (2026) gathered 14 patients with muscle imaging (12 adults and 2 children): all had fatty replacement predominantly in the lower limbs; the gluteus maximus and medius and the tensor fasciae latae were affected in all; the sartorius, gracilis and rectus femoris had severe replacement in all adults and less severe replacement in the children; the vastus lateralis was severely affected in all; and, in the leg, the posterior compartment was affected with relative sparing of the tibialis anterior and posterior [47]. In adults there was an anteroposterior gradient in the thigh, and in children a mild posteroanterior gradient; the paraspinal and gluteal muscles were severely affected, with a Trendelenburg gait in the child described [47]. In this series, all seven biopsies (between 18 months and 54 years of age) were myopathic-dystrophic with rimmed vacuoles, and electromyography was myopathic in the 10 adults studied [47].

3.4. Eye

The cataracts are bilateral, not necessarily congenital, and may develop rapidly; the mean age at onset is about 3.5 years and lens extraction is usually required in the first decade [1]. In Japan, cataracts appeared and progressed rapidly in all 24 patients with SIL1 variants, at a mean age of 3.5 ± 1.2 years, and all required early surgery [9]. In the review by Krieger and colleagues, cataracts were present in all patients older than 7 years and could be absent in infancy [35]. Strabismus affects at least half of patients [1, 9]. Ezgu and colleagues described iris coloboma among the additional features [51]. Saudubray describes the cataract of MSS as congenital [18]; GeneReviews and the molecularly studied cohorts show that, in most cases, the cataract is acquired in the first years of life, and this is the definition adopted [1, 9].

3.5. Development and cognition

Intellectual abilities range from normal to severe intellectual disability, although more than 90% of patients have intellectual disability [1]. In Japan, 91% (20/22) had mild to moderate intellectual disability (IQ/DQ 35–70), first words appeared at 2.0 ± 0.8 years and most attended special education [9]. Six patients with SIL1 variants and normal intelligence led Krieger and colleagues to recommend SIL1 testing in patients with a compatible phenotype without intellectual disability [35]; the Turkish patient of Aslan and colleagues, with c.453+1G>T, had normal cognition at 21 years of age [34].

3.6. Endocrine system, growth and skeleton

Hypergonadotrophic (primary) hypogonadism and delayed puberty are common, without associated congenital genital anomalies [1]. In the muscle imaging review, 10 of 12 adults had hypergonadotrophic hypogonadism [47]. The Japanese article designates as "hypogonadotrophic" the hypogonadism of 3 of 8 patients (one with microtestis, two with amenorrhoea), without published gonadotrophin measurements [9]; GeneReviews and the Buchignani series describe it as hypergonadotrophic, and the distinction is useful in the differential diagnosis with CCFDN, in which the hypogonadism is hypogonadotrophic [1, 2, 47]. An adult Japanese patient with primary hypogonadism had low bone mass [55]. In a magnetic resonance imaging (MRI) study of five patients with a clinical diagnosis of MSS (pre-SIL1 era), the adenohypophysis appeared small in two and the hyperintense signal of the neurohypophysis was absent in three, without associated endocrine dysfunction [56].

Short stature affects 50–70% and there is occasional microcephaly [1]. Scoliosis of variable degree is common, together with shortening of metacarpals, metatarsals and phalanges, coxa valga, pes planovalgus and pectus carinatum; skeletal severity appears to correlate with overall severity [1]. Reinker and colleagues described two patients in Hawaii with multiple physeal growth arrests, bilateral hypoplasia of the lateral femoral condyles with progressive valgus, patellar dislocation and quadriceps dysfunction, and argue that timely orthopaedic intervention may prolong walking [57]. Ezgu and colleagues added dental anomalies, eczema and hormonal abnormalities [51].

3.7. Other systems and life expectancy

No Japanese patient had cardiac or respiratory problems, and respiratory, cardiac and swallowing functions were preserved even beyond 50 years of age [9]. Life expectancy appears to be near normal [1]. The sources consulted do not describe urinary symptoms in MSS; for the ataxias in general, ERN-RND recommends asking about them (section 11) [58].

3.8. Variability and historical spectrum

The 2004 ENMC review of clinical descriptions of MSS recorded, in cases published before molecular study, sensorimotor or segmental demyelinating peripheral neuropathy, mild brainstem atrophy, leucoencephalopathy, a small adenohypophysis, epilepsy and cerebellar dysplasia, and concluded that clinical MSS was heterogeneous, with cases overlapping with CCFDN [30]. These features, described in series without SIL1 confirmation, should not be attributed to SIL1-related MSS without molecular confirmation.

4. Clinical Recognition and Warning Signs

4.1. When to suspect

MSS should be considered in the presence of cerebellar ataxia, dysarthria and nystagmus; early-onset cataracts; muscle weakness and hypotonia; psychomotor delay; hypergonadotrophic hypogonadism; short stature; and skeletal anomalies such as scoliosis, shortening of metacarpals, metatarsals and phalanges, coxa valga, pes planovalgus and pectus carinatum [1]. A family history compatible with recessive inheritance (affected siblings, consanguinity) strengthens the suspicion, but its absence does not exclude it [1]. Ophthalmological examination is part of the assessment of any child or adult with ataxia: in the ataxic child, cataract points to MSS, just as conjunctival telangiectasias point to ataxia-telangiectasia, retinopathy to spinocerebellar ataxia type 7 (SCA7), abetalipoproteinaemia or neuropathy, ataxia and retinitis pigmentosa (NARP) syndrome, and optic atrophy to Friedreich ataxia or infantile-onset spinocerebellar ataxia (IOSCA) [59, 60].

4.2. Warning signs for other diagnoses

Some findings argue against SIL1-related MSS and point to a specific differential diagnosis. Microcornea and microphthalmia in a Roma infant with congenital cataracts make CCFDN very likely, and slowing of nerve conduction velocities after 18 months of age confirms this orientation [2]. An episode of acute proximal weakness with myalgia and dark urine after a febrile illness suggests the parainfectious rhabdomyolysis of CCFDN and requires urgent assessment [2, 62]. Lower-limb spasticity, urge incontinence and axonal neuropathy with initially normal development point to GBA2 [21]. Onset of symptoms after the first decade, with juvenile cataract and cerebellar signs, suggests cerebrotendinous xanthomatosis (CTX), even without tendon xanthomas, which is treatable [20]. Normal brain MRI in a child with muscular dystrophy, cataract and intellectual disability points to INPP5K [1, 31]. Encephalopathy, seizures, stroke-like episodes, raised lactate or cardiomyopathy suggest mitochondrial disease [1].

4.3. Urgent signs

The cataracts of MSS appear abruptly and progress quickly, so visual loss within a few months is the main functional emergency in childhood and justifies ophthalmological examination from an early age [9]. Choking, poor weight gain, food refusal or recurrent respiratory infections justify a swallowing assessment [1]. In CCFDN, any sign of rhabdomyolysis (acute weakness, myoglobinuria) requires urgent assessment [2]. The sources consulted do not describe newborn screening for MSS or for CCFDN.

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

No published consensus clinical criteria exist [1]. GeneReviews allows two routes: clinical diagnosis, based on suggestive findings and the ultrastructural changes on muscle biopsy, considered specific to MSS; and molecular diagnosis, by identification of biallelic pathogenic or likely pathogenic variants in SIL1 [1]. The identification of two VUS, or of one pathogenic variant and one VUS, neither establishes nor excludes the diagnosis, according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [1]. The Chinese case with two SIL1 VUS and functional reduction of the protein illustrates this intermediate zone: the authors refer to MSS, but the classification of the variants does not by itself confirm the diagnosis [49].

5.2. Neuroimaging

Brain MRI shows cerebellar atrophy, usually more marked in the vermis than in the hemispheres, and T2 hyperintensity of the cerebellar cortex [1, 63]. The age at onset of the atrophy is unknown; the youngest patients studied were small children, and the expected progression has not been confirmed by serial MRI [1]. Cerebellar atrophy was found in all patients with SIL1 variants studied in Japan (19/19) [9]. In a study of five patients with a clinical diagnosis predating SIL1, only two had mild cerebellar atrophy, and the authors concluded that severe atrophy is not obligatory [56]; as the genetic status of these patients is unknown, an MRI without cerebellar atrophy requires reconsideration of the differential diagnosis (CCFDN, INPP5K, Schulz MSS-like) before maintaining the hypothesis of MSS [1, 32]. The pattern of "cerebellar atrophy with T2 hyperintensity of the cerebellar cortex" is not exclusive to MSS: it also occurs in some mitochondrial disorders, coenzyme Q10 deficiency, infantile neuroaxonal dystrophy, PMM2 congenital disorder of glycosylation (PMM2-CDG), late-infantile neuronal ceroid lipofuscinosis, pontocerebellar hypoplasia type 7 and Christianson syndrome [19].

Muscle imaging shows severe, dystrophic-type replacement of muscle by fat and connective tissue [1, 54]. Axial T1 muscle MRI at 3 T, with the pattern described in section 3.3 (gluteal muscles, tensor fasciae latae, sartorius, gracilis, vastus lateralis, posterior compartment of the leg with relative sparing of the tibialis muscles), has been proposed as a complementary non-invasive examination and possible biomarker of progression, without prospective validation [47].

5.3. Laboratory, neurophysiology and muscle biopsy

Serum creatine kinase (CK) is normal or moderately raised, usually 2 to 4 times the upper limit of normal [1]; in Japan it ranged from 28 to 2000 IU/L (mean 389 ± 464 IU/L; normal <200 IU/L) [9]. Electromyography (EMG) shows only myopathic features [1]. On light microscopy, the muscle biopsy is non-specific: fibre size variation, atrophic fibres, fatty replacement and rimmed vacuoles [1]. In Japan, rimmed vacuoles (modified Gomori trichrome stain) were present in 16 of 16 biopsies from patients with SIL1 variants, with endomysial fibrosis and rare necrotic or regenerating fibres, without neurogenic changes; in one patient without a SIL1 variant there were no vacuoles [9]. Rimmed vacuoles are rare in childhood myopathies, so the biopsy may bring forward the diagnosis and cataract surgery [9]. Electron microscopy shows autophagic vacuoles, membranous whorls and electron-dense double-membrane structures associated with the nuclei, an ultrastructural feature considered specific to MSS [1]. In a series of 34 children with undiagnosed congenital or late-onset ataxia and cerebellar atrophy, muscle biopsy found reduced coenzyme Q10 in 9 and, in a 2.5-year-old child with non-syndromic congenital ataxia, autophagic vacuoles that led to the diagnosis of MSS due to homozygous SIL1 p.(Arg111Ter) before the appearance of cataracts [46]. Cytoplasmic inclusions in cultured fibroblasts are a research marker, not a clinical test [51].

5.4. Genetic testing

The strategy may start from a single gene or from multigene tests [1]. In single-gene testing, SIL1 is sequenced first; if one or no variant is found, targeted deletion and duplication analysis follows (quantitative or long-range polymerase chain reaction, PCR, multiplex ligation-dependent probe amplification, MLPA, or targeted microarray); in people of Finnish ancestry, testing may start with the founder variant [1]. Neuromuscular disease, myopathy, ataxia or cataract panels that include SIL1, and the exome, are alternatives; the exome is the most widely used option and the genome is reserved for atypical phenotypes, because most known variants are coding [1]. The ERN-RND European network flowchart for early-onset ataxias (2020) proposes: clinical and family history; assessment with the Inventory of Non-Ataxia Signs (INAS) and an ataxia scale, such as SARA (Scale for the Assessment and Rating of Ataxia); brain MRI and neurophysiology; exclusion of mimics and acquired ataxias; for a distinctive phenotype, targeted laboratory investigation, chromosomal microarray and single-gene or panel sequencing; if negative, repeat expansion disorders and exome or genome, which may be started in parallel immediately after MRI; and, if still negative, mitochondrial DNA sequencing, microarray, karyotype and data reanalysis [64].

GeneReviews presents the proportion of pathogenic variants detected by method, based on the Human Gene Mutation Database (HGMD) [1]:

These figures are proportions of recorded variants and of patients without a SIL1 cause; they are not the clinical sensitivity of the test. Sensitivity depends on the entry phenotype: 60% with the triad of ataxia, cataract and myopathy versus less than 3% with partial presentations [35], and 89% in a Japanese national series with a founder effect [9].

5.5. Limitations of testing

Sequencing may not detect deletions of one or more exons, and apparent homozygosity may correspond to a variant on one allele and a deletion on the other, or to uniparental isodisomy [1]. Variants in the promoter and other non-coding regions were not excluded in the Japanese patients without SIL1 variants [9]. The CCFDN variant is deep intronic (c.863+389C>T) and GeneReviews indicates that sequencing must include deep intronic variants [2]; an exome focused on coding regions and exon-intron junctions may not detect it, so when there is suspicion, targeted testing or the genome is used. A negative SIL1 result does not exclude a clinical diagnosis of MSS [4]. The exome may reveal a second diagnosis that modifies the phenotype, such as concomitant dysferlinopathy [48].

5.6. Report and interpretation

The report should state the gene, the versioned transcript (NM_022464.5 for SIL1; NM_004715.5 for CTDP1), the HGVS nomenclature of the variant at coding DNA and protein level, zygosity, the ACMG/AMP classification and, where applicable, confirmation that the two variants are in trans by parental testing [1, 33]. Historical notation should be converted (for example, c.506_509dupAAGA to c.506_509dup; IVS6+389C>T to c.863+389C>T) [1, 2]. For VUS, segregation analysis, muscle ultrastructure and functional studies (SIL1 expression in lymphoblasts or fibroblasts, interaction with BiP) support reclassification, as occurred with p.(Glu342Lys) [49, 50].

5.7. Practical algorithm

NCV: nerve conduction velocity.

5.8. Prenatal and preimplantation diagnosis

When both pathogenic variants in the family have been identified, prenatal diagnosis and preimplantation genetic testing are possible [1]. In one of the published cases, the second sibling was diagnosed with MSS during fetal life [47]. Prenatal ultrasound is not a diagnostic means described in the sources consulted.

6. Differential Diagnosis

6.1. Comparative overview

The differential diagnosis of MSS is organised around three combinations: ataxia with cataract, cataract with myopathy, and ataxia with myopathy. The table brings together the entities in the GeneReviews chapters on MSS and CCFDN and the phenocopies published as "MSS" or "MSS-like".

AD: autosomal dominant; CSF: cerebrospinal fluid.

6.2. CTDP1-related CCFDN

Clinical features

CCFDN is the entity most often confused with MSS in the literature before 2002, and its diagnosis changes management (rhabdomyolysis, anaesthesia, eye surgery). All patients and carriers identified are Roma [2]. Congenital cataracts are the first, invariable manifestation; they are bilateral, anterior or posterior subcapsular with opacification of the adjacent nucleus, or total, and are associated with microcornea, microphthalmia (by axial length) and micropupils with fibrotic margins, which constrict slowly to light and dilate slowly with mydriatics; horizontal pendular nystagmus is very common and unrelated to the visual deficit; the fundus is normal [2]. In a series of nine patients, cataracts were diagnosed at a mean of 3.4 weeks, microcornea and microphthalmia were present in all, and surgery was complicated by micropupils, increased inflammatory and foreign-body reactions, pupillary occlusion membranes and secondary cataracts with frequent reoperations; eyelid changes (floppy eyelid) and contact lens intolerance led to chronic papillary conjunctivitis, meibomian gland dysfunction and pseudoptosis in adolescence [30].

Source: GeneReviews chapter on CCFDN [2].

In a study of 28 children aged between 4 months and 16 years, motor delay was invariable and all began walking between 2 and 3 years of age, often with an unsteady gait; signs of lower-limb motor neuropathy (reduced or absent reflexes, distal weakness, foot deformities) appeared after 4 years, followed by the upper limbs, and lower-limb numbness after 10 years [2, 30]. Cerebellar ataxia was present in six children older than 6 years [30]. All adults have deformities (pes cavus, equinovarus foot, flexion contractures of the interphalangeal joints), and scoliosis or kyphosis may reduce respiratory capacity [2]. Conduction velocity is normal in infancy, decreases after 18 months and stabilises at about 20 m/s between 4 and 10 years; distal motor latencies increase; sensory potentials initially have normal amplitude (uniform slowing of a congenital hypomyelination) and then decrease, and sural potentials may disappear after 10 years owing to secondary axonal loss [2, 62]. Sural nerve biopsy shows primary hypomyelination without Schwann cell or axonal abnormalities [2]. In the cohort of Walter and colleagues (16 patients followed for 10 years, Munich and Vienna), paresis of the small hand muscles and foot extensors worsened in all, while ataxia scales remained stable or improved, and the authors proposed classifying CCFDN as a recessive demyelinating sensorimotor neuropathy, with axonal loss as the determinant of disability [62].

Speech appears at about 3 years; about 10% of patients have normal or borderline cognitive performance and the rest mild non-progressive intellectual disability, with verbal memory, executive functions and language equally affected; interpretation should take into account visual impairment, limited schooling and the language barrier [2]. In a cohort of 22 confirmed patients, 18 had mild intellectual disability and 4 borderline intelligence, with diffuse cerebral atrophy, ventricular dilatation and subcortical white matter lesions, more marked with age [5, 68]. Some patients have pyramidal signs without spasticity and extrapyramidal hyperkinesias [2]. MRI shows cerebral, cerebellar and cervical spinal cord hypotrophy in childhood, cerebral atrophy with ventricular dilatation, occasionally a thin corpus callosum and cerebellar atrophy, and multifocal periventricular and brainstem T2 hyperintensities; diffusion tensor imaging suggests axonal loss in the vermis and medulla [2]. In a study of 12 patients presented at the ENMC, conventional MRI was normal and only diffusion tensor imaging showed changes in the vermis and medulla [30].

Growth deficiency begins in utero. In 22 term newborns, boys weighed 3.22 ± 0.48 kg (reference 3.9 ± 0.5 kg) and measured 47.88 ± 3.91 cm (reference 53.1 ± 2.1 cm), and girls 3.06 ± 0.53 kg (reference 3.8 ± 0.6 kg) and 46.75 ± 4.19 cm (reference 52.5 ± 2.1 cm); in adults, men measured 149.2 ± 5 cm and weighed 47 ± 7.2 kg (reference 173 ± 6.8 cm and 73.9 ± 10.4 kg) and women 142.4 ± 8.2 cm and 45.8 ± 7.6 kg (reference 160.3 ± 6.4 cm and 63 ± 10.7 kg) [2]. Growth hormone is at the lower limit of normal, with a marked rise after insulin hypoglycaemia, indicating a mild regulatory deficiency [2]. Sexual development and menarche appear normal, but most adult women have irregular cycles and early secondary amenorrhoea between 25 and 35 years of age, and more than half of adults have hypogonadotrophic hypogonadism (low testosterone and subnormal follicle-stimulating hormone, FSH, in men; low oestradiol and subnormal luteinising hormone, LH, in women); bone mineral density is reduced and the impact on fertility has not been assessed [2].

Parainfectious rhabdomyolysis is probably an integral part of the phenotype: after a febrile illness, especially viral, severe acute proximal weakness and myalgia appear (proximal weakness is not typical outside episodes), with myoglobinuria and very high CK [2]. Episodes are usually recurrent and resolve spontaneously without acute kidney injury, although the GeneReviews summary describes them as potentially fatal; recovery may take up to a year and repeated episodes may worsen the neuropathy [2]. In the Walter cohort, 6 of 16 patients had these episodes, with a worse course and permanent loss of ambulation in 3 [62]. EMG during rhabdomyolysis showed proximal myogenic changes that disappeared after recovery, and the muscle biopsy shows mild myopathy with scattered necrotic fibres, normal myophosphorylase and phosphofructokinase and no mitochondrial pathology [2]. Prolonged exercise caused myalgia in one patient [2].

Distinction from MSS

The best discriminators between CCFDN and MSS are ophthalmological examination (extensive anterior segment involvement in CCFDN), neurophysiology (reduced NCV in CCFDN), neuroimaging (cerebellar atrophy in MSS) and the ultrastructure of the muscle biopsy, which is specific to MSS [2]. The hypogonadism is hypogonadotrophic in CCFDN and hypergonadotrophic in MSS [1, 2]. In an infant with isolated bilateral cataracts, microcornea and microphthalmia make CCFDN very likely, and developmental delay and neuropathy narrow the differential; in Roma infants, the main differential of CCFDN is galactokinase deficiency due to the founder variant GALK1 NM_000154.2:c.82C>A p.(Pro28Thr) [2, 33]. CTDP1 was identified in 0.8% of a hereditary neuropathy cohort, mainly in the demyelinating subtypes of Charcot-Marie-Tooth disease type 1 (CMT1), and is among the recessive CMT genes, so it should be included in demyelinating neuropathy panels [69].

Diagnosis and assessment

Diagnosis is made by targeted testing for c.863+389C>T, which accounts for 100% of reported variants, first in patients of Roma ancestry; no deletions or duplications have been described [2]. Useful non-molecular tests are ophthalmological examination, NCV (historically confirmed by nerve biopsy), brain MRI, CK and urinary myoglobin when rhabdomyolysis is suspected, gonadotrophin and sex steroid measurements and psychometric assessment [5]. The initial assessment includes ophthalmological examination; neurological examination with conduction velocities; orthopaedics, physical medicine and rehabilitation, physiotherapy and occupational therapy; developmental assessment; endocrinology (growth, fertility, osteopenia); and genetic counselling [2].

Management

There are no published guidelines [2]. The 125th ENMC workshop (Naarden, 2004) agreed on collaborative research into the cerebral effects of the variant, the frequency and triggers of rhabdomyolysis and the management of ocular manifestations, and on the creation of central diagnostic services in Europe [30]. The management described by GeneReviews is as follows [2]:

GeneReviews and the 2014 Walter abstract do not state the corticosteroid or the dose used [2, 62]. There is no validated dose for this indication. As a label reference, and with declared extrapolation, oral prednisone has an initial dose of 5 to 60 mg per day depending on the disease treated, to be individualised and reduced in decrements after response [71]. The Walter cohort recommends counselling patients about virus-triggered rhabdomyolysis and the risk of malignant hyperthermia; supplementation with fat-soluble vitamins was presented as a hypothesis for study [62]. Surveillance includes ophthalmology annually or as advised by the ophthalmologist, neurology annually, orthopaedics and rehabilitation as needed, development at each visit during childhood and endocrinology annually (growth, fertility, osteopenia) [2]. Older and younger siblings of a patient should be assessed for early ophthalmological, neurological and endocrine treatment [2]. Only three women with CCFDN have had children described, with uneventful term pregnancies [2].

Research

There is no approved drug for CCFDN [5]. The only registered study is observational (NCT01902940, Natural History in CCFDN and IBM Syndromes, Ludwig-Maximilians-Universität Munich), retrospective, completed in 2013, with 350 participants including patients with inclusion body myopathies, with no results in the registry [12]. The review by Sabau and colleagues (2025) discusses purely conceptual approaches for the founder variant: antisense oligonucleotides blocking the cryptic site (on the nusinersen model), small-molecule splicing modulators (on the risdiplam model), gene replacement with adeno-associated virus (AAV; the cDNA of about 3.5 kb is compatible), genome editing and oligonucleotides targeting a uORF in the 5′ untranslated region to increase translation of the normal transcript, which accounts for about 30% of the protein in patients; the review presents no experimental data of its own [69].

Epidemiology and counselling

CCFDN was described in Bulgaria, where more than 70 cases had been investigated by 2004, and has been diagnosed in several European countries [30]. The variant is exclusive to the Vlax Roma subgroup, with a carrier frequency of about 7% among the Rudari and about 1.4% in the Roma population in general [2, 69, 72]; the haplotype was absent in 832 non-Vlax and European controls [69]. No carriers were found among the Croatian Bayash Roma studied (427 screened in total; 250 tested for CCFDN, according to Sabau) [5, 69, 73]. In the Czech Republic, ten Roma children were diagnosed in a series that describes CCFDN as a frequent and underestimated cause of disability [2, 69]. Inheritance is autosomal recessive, with a 25% risk for each sibling; in endogamous Roma communities with consanguinity, carrier testing in the extended families of both parents and in future partners of carriers is justified, and prenatal diagnosis and preimplantation genetic testing are possible [2]. In Bulgaria, community pilot carrier testing programmes included an educational component, screening for several founder variants, genetic counselling, prenatal diagnosis of at-risk pregnancies and training of Roma mediators [30].

6.3. Spastic paraplegia 46 and GBA2-related MSS-like syndrome

Deficiency of non-lysosomal β-glucosidase (GBA2) causes recessive cerebellar ataxia and hereditary spastic paraplegia type 46 (SPG46, OMIM 614409); most patients have marked lower-limb spasticity in childhood, progressive gait impairment and then ataxia and cerebellar signs, with deafness, cognitive impairment or an MSS picture in some, and testicular hypotrophy and sperm head abnormalities in others [65]. Haugarvoll and colleagues studied two families from western Norway, one of them published as MSS in 1977, and an apparently unrelated patient, with consanguineous links in parish records; the three patients were 70, 48 and 51 years old at last observation and were homozygous for NM_020944.3:c.1528_1529del p.(Met510ValfsTer17) in exon 9 [21, 74]. Early development was normal, onset occurred between 5 and 7 years of age and the course was slowly progressive to severe spasticity, severe ataxia, urinary incontinence and severe dysarthria, with wheelchair dependence in all; there was axonal or mixed neuropathy, a neurogenic muscle biopsy, normal CK and cataracts sometimes only in adulthood, operated on at 26 and 49 years of age [21]. Glucosylceramide was markedly raised in erythrocytes (15.7–23.8 µmol/L versus 1.8–6.0 µmol/L in controls) and in plasma (27.2–37.4 versus 4.7–9.7 µmol/L), at levels similar to or higher than those of untreated patients with Gaucher disease, with normal lymphocyte glucocerebrosidase and chitotriosidase; GBA2 activity in leucocytes was 7% of control, and fibroblasts are not suitable for this assay [21]. The authors recommend testing GBA2 in MSS-like syndromes [21]. About 30 families with SPG46 have been described worldwide; the largest Italian series, of five patients, added supranuclear upgaze palsy and movement disorders to the spectrum [75]. Spastic paraplegia 46 is included in the differential diagnosis.

6.4. INPP5K-related congenital muscular dystrophy

Osborn and colleagues described five patients from four families with muscular dystrophy and reduced dystroglycan glycosylation, short stature, intellectual disability and cataracts, overlapping with the dystroglycanopathies and MSS, with homozygous missense or compound heterozygous variants in INPP5K [31]. INPP5K (also called SKIP) is an inositol polyphosphate 5-phosphatase expressed in brain and muscle, located in the ER and in cytoplasmic actin ruffles, which interacts with the HSPA5/BiP chaperone, bringing its pathogenesis close to that of MSS [31]. The GeneReviews chapter on MSS distinguishes it by normal brain MRI and absence of ataxia [1]. The convergence of the two disorders on PHGDH dysregulation is described in section 2.2 [41]. The dystroglycanopathies are included in the differential diagnosis.

6.5. Cerebrotendinous xanthomatosis

Siebner and colleagues described a 39-year-old patient with cerebellar signs, juvenile cataracts and borderline intelligence, previously diagnosed as MSS, who had CTX without tendon xanthomas, confirmed by markedly increased urinary excretion of bile alcohols [20]. CTX is a sterol storage disorder due to autosomal recessive sterol 27-hydroxylase deficiency, with raised cholestanol in several tissues; onset after the first decade favours CTX, but clinical distinction may be difficult, and the authors consider that some patients published as MSS had CTX [20]. The relevance is therapeutic, because CTX is treatable [20]. Measurement of cholestanol or urinary bile alcohols should precede a clinical diagnosis of MSS without molecular confirmation. CTX is included in the differential diagnosis.

6.6. MSS-like phenotypes without an identified gene and other entities

Schulz and colleagues described two German siblings with congenital cataract, ataxia, motor delay and intellectual disability similar to those of MSS, but without marked cerebellar atrophy, with external ophthalmoplegia and paralytic dysphagia, and without variants in the 10 exons of SIL1 [32]. Cataract-ataxia-deafness syndrome (ORPHA:1368) has two cases in Orphanet: two Dutch sisters with intellectual disability, congenital cataract, progressive spinocerebellar ataxia, sensorineural deafness and polyneuropathy evident in the third decade [8, 66]. In the Japanese patients without SIL1 variants the picture was indistinguishable, and the absence of rimmed vacuoles in one of them suggests another mechanism [9]. The association of hypogonadism with movement disorders was reviewed by González-Latapi and colleagues, who include these entities in a broader group of syndromes with hypogonadism and ataxia [76]. In 2004 the ENMC recorded a form of MSS associated with chylomicron retention disease, linked to the SARA2 gene at 5q31 [30]; the hypobetalipoproteinaemias with ataxia are also included in the differential diagnosis.

6.7. Cellular trafficking disorders with cataract and myopathy

Saudubray lists SIL1 among the vesicular trafficking disorders associated with cataract (with Lowe syndrome due to OCRL, multiple sulfatase deficiency due to SUMF1, Vici syndrome due to EPG5, Warburg micro syndrome due to RAB3GAP1, RAB18 and TBC1D20, and Yunis-Varon syndrome due to FIG4, VAC14 and WFS1), muscle abnormalities (with LPIN1, MTMR14, LAMP2, TANGO2 and EPG5) and genital or reproductive abnormalities (with Carpenter, Martsolf and Warburg micro syndromes) [18]. Lowe syndrome and the other syndromic cataracts are included in the differential diagnosis.

7. Treatments and Risk Management Strategies

7.1. Principles

There is no disease-modifying therapy, and no clinical practice guidelines have been published for MSS; the GeneReviews recommendations are based on the author's experience, and the available evidence is expert opinion [1, 4]. Care is supportive and ideally multidisciplinary [1]. The drug doses presented come from official labels or from guidelines for analogous conditions, and their use in MSS is off-label, with the extrapolation declared in each case.

7.2. Cataracts and strabismus

The cataracts of MSS usually require lens extraction in the first decade [1]. Because they appear abruptly and progress quickly, all Japanese patients required early surgery, and the authors recommend careful ophthalmological examination from a young age to preserve visual acuity [9]. The sources consulted do not describe postoperative complications specific to MSS; the exaggerated inflammatory reaction and contact lens intolerance described in CCFDN (section 6.2) are not documented in MSS [2, 30]. Strabismus is treated as advised by the ophthalmologist [1].

7.3. Rehabilitation, feeding, communication and education

Physiotherapy aims to maximise mobility and reduce the risk of late orthopaedic complications such as contractures, scoliosis and hip dislocation; assistive equipment includes wheelchairs, walkers, bath chairs, orthoses and adapted strollers [1]. Occupational therapy works on the fine motor skills needed for feeding, grooming, dressing and writing [1]. Oromotor dysfunction should be assessed at each visit; choking, poor weight gain, frequent respiratory infections or food refusal justify a clinical feeding assessment and/or a radiological swallowing study, with feeding therapy, thickened or chilled foods and, if the dysfunction is severe, a nasogastric tube or gastrostomy [1]. Augmentative and alternative communication (AAC), from low to high technology, should be considered and does not impair speech development [1]. In the GeneReviews model, defined for the United States, early intervention (occupational, physical, speech and feeding therapy, special education and sensory support) covers ages 0 to 3 years, followed by preschool education with an individualised education plan from 3 to 5 years, and at all ages there is follow-up by a developmental paediatrician, an education plan reviewed annually, vision consultants and transition planning in adolescence [1]. In Portugal and Brazil, the national early intervention and inclusive education systems apply, which the sources consulted do not describe.

7.4. Pubertal induction and hormone replacement

GeneReviews recommends hormone replacement therapy at the expected age of puberty, without specifying drugs or doses [1]. The analogous condition with a guideline is congenital primary hypogonadism (gonadal insufficiency), covered by the 2022 guideline of the European Reference Network on Rare Endocrine Conditions (Endo-ERN), endorsed by the European Society for Paediatric Endocrinology (ESPE), the European Society of Endocrinology (ESE) and the European Academy of Andrology (EAA), with GRADE grading [61]. The extrapolation to MSS is declared: the guideline does not include patients with MSS, and the decision should weigh each patient's mobility, bone density and growth.

The guideline recommends a multidisciplinary team (paediatric and adult endocrinology, psychology, urology, gynaecology, genetics, surgery and nursing) [61]. In girls, it recommends specialist assessment of any girl without pubertal signs at 13 years, with delayed puberty (<−2 SD) or, from 8 years, with a condition at risk of hypogonadism; induction may be considered at 11 years if hypogonadism is confirmed and there are no pubertal signs (at 13 years if constitutional delay is suspected), after excluding spontaneous puberty and treatable causes; replacement is also started if spontaneous puberty does not progress; 17β-oestradiol is used, with follow-up every 3–6 months and titration according to pubertal progression; a progestogen is added after the first withdrawal bleed or after at least 2 years of treatment; at the end of induction (2–3 years) the patient moves to permanent adult replacement; and in late diagnosis the escalation should be individualised and as rapid as possible [61]. In boys, it recommends assessment if puberty is delayed (<−2 SD), with no signs at 14 years or with inadequate progression, and pubertal assessment from 9 years in at-risk conditions; all boys with permanent hypogonadism should undergo induction, which may begin at 12 years if there are no pubertal signs, with testosterone, structured endocrine assessment at baseline and during follow-up, adjustment of dose or route in the event of adverse effects and monitoring for gynaecomastia [61].

The recommended doses are those of the Endo-ERN guideline, by extrapolation from the analogous condition; the official labels (FDA and INFARMED SmPC) are given for comparison, and the "Relation to the label" column indicates how they differ. The labels have no paediatric indication for pubertal induction with oestrogens, and the guideline's starting doses are therefore outside the label conditions.

Doses recommended by the Endo-ERN guideline and relation to the label:

The starting doses apply to pubertal induction in adolescents with hypogonadism (oestrogen from about 11 years of age in girls with a known cause); the guideline titrates up to the adult replacement dose, which serves as the target, with no maximum dose defined in the source [61].

Doses in the official labels (comparison):

The guideline notes that oestrogen formulations are adult formulations and that their paediatric use is off-label [61]. During induction, examination (weight, height, blood pressure, Tanner stage) is performed every 3–6 months, with bone age and hormone measurements at baseline; with testosterone, pubertal and skeletal maturation, growth velocity, haematocrit, liver function, gynaecomastia, priapism and behaviour are monitored [61].

The official labels, cited for comparison, state the following. In the United States, testosterone enanthate is indicated for primary and hypogonadotrophic hypogonadism and for delayed puberty in selected boys: in male hypogonadism, 50 to 400 mg every 2 to 4 weeks; in delayed puberty, 50 to 200 mg every 2 to 4 weeks for a limited period, for example 4 to 6 months; injections at intervals of less than 2 weeks are rarely indicated and total doses above 400 mg per month are not needed; in paediatrics it should be used with great caution and by specialists, with a hand and wrist radiograph every 6 months to assess bone maturation [77]. Testosterone cypionate (Depo-Testosterone®) has a dose of 50 to 400 mg every 2 to 4 weeks in the hypogonadal man, with safety and efficacy not established below 12 years of age [78]. In Portugal, Sustenon® 250 mg/1 ml (a mixture of testosterone propionate, phenylpropionate, isocaproate and decanoate in arachis oil) is indicated for replacement in confirmed male hypogonadism, with an injection of 1 ml every three weeks in adults; paediatric safety and efficacy are not established and prepubertal children should be treated with caution; it is contraindicated in peanut or soya allergy, breast or prostate cancer and pregnancy; monitoring of testosterone, haematocrit and haemoglobin, liver function and lipid profile is recommended, quarterly in the first year and annually thereafter [79]. Testogel® 50 mg (transdermal gel, 5 g sachet) is authorised in Portugal for adult men with confirmed hypogonadism, at a dose of 5 g of gel (50 mg of testosterone) once daily, preferably in the morning, adjusted in 2.5 g steps up to a maximum of 10 g of gel (100 mg) per day, with measurement of morning serum testosterone from day 3 (one week is reasonable); safety and efficacy below 18 years are not established, it is not indicated in women, and people in close contact, including children, should not touch the application site [80]. In Portugal, the SmPCs of oestradiol (Dermestril®, Estrofem®, Zumenon®) and progesterone (Utrogestan®) have indications only after the menopause and for progesterone insufficiency in adults, so pubertal induction with these drugs is off-label use [81–84]. The sources consulted do not include the Brazilian package inserts for these drugs.

7.5. Bone health

Hormone replacement therapy may help prevent osteoporosis [1]. In an adult Japanese patient with MSS, primary hypogonadism and low bone mass, testosterone combined with risedronate did not change muscle strength or muscle MRI, but bone mass improved and continued to improve with risedronate alone; after 3 years the muscle pattern was unchanged and bone density had increased [47, 55]. The authors consider bisphosphonates probably beneficial for low bone mass in MSS, based on a single patient [55]. Risedronate sodium (Actonel®) is authorised in the United States for osteoporosis in men (35 mg once weekly) and postmenopausal osteoporosis (5 mg/day, 35 mg/week, 75 mg on 2 consecutive days per month or 150 mg per month); it is taken with 180–240 mL of water at least 30 minutes before the first food, without lying down for the next 30 minutes, with calcium and vitamin D supplementation if intake is insufficient, and it is not indicated in paediatrics [85]. Use in MSS is extrapolated from osteoporosis and is off-label; the label administration conditions (upright position for 30 minutes after ingestion) should be weighed in a patient with dysphagia or difficulty sitting upright [85].

7.6. Hypertonia, dystonia and spasticity

GeneReviews states that, in the presence of hypertonia or dystonia, specialist guidance should be considered for baclofen, tizanidine, botulinum toxin (Botox®), antiparkinsonian drugs or orthopaedic procedures [1]. Spasticity is not a cardinal feature of MSS, and pyramidal signs are "modestly constant" [35]. In a disease with myopathic weakness, the labels warn of the risk of weakness and falls when tone is needed for posture and gait (baclofen) and of the spread of toxin effect with dysphagia and breathing difficulty [86, 87]. GeneReviews does not specify the antiparkinsonian drugs, so there is no dose to indicate.

The pivotal trials of botulinum toxin in paediatric spasticity included 234 children for the upper limb (78 with 3 U/kg, 77 with 6 U/kg, 79 with placebo) and 382 for the lower limb (126 with 4 U/kg, 128 with 8 U/kg, 128 with placebo); upper respiratory tract infection occurred in 17% with 6 U/kg versus 9% with placebo, and seizures in 5% versus 0% [87]. These data come from cerebral palsy and have not been studied in MSS.

7.7. Orthopaedics

Scoliosis and the other skeletal manifestations are treated as advised by the orthopaedic surgeon [1]. In patients with multiple physeal growth arrests and hypoplasia of the lateral femoral condyles, progressive valgus, patellar dislocation and quadriceps dysfunction justify surveillance and timely orthopaedic intervention, which may prolong walking [57]. Physiotherapy helps reduce contractures, scoliosis and hip dislocation [1].

7.8. Comparative regulatory status

No medicinal product has an approved indication for MSS or CCFDN [4, 5]. The European Medicines Agency (EMA) list of orphan designations, consulted on 26 October 2026 (3310 designations), contained no designation for MSS, SIL1, CCFDN or CTDP1; the sources consulted do not include the Food and Drug Administration (FDA) orphan designation database, and a negative search does not demonstrate the absence of designations. The table compares the labels of supportive drugs in the United States and Portugal, in the analogous indications.

The sources consulted do not include the Brazilian (ANVISA) package inserts for these drugs.

7.9. Clinical trials and research

There are no registered interventional trials for MSS. A ClinicalTrials.gov search on 26 October 2026 found only a generic rare disease and natural history registry that includes MSS in its list of conditions (NCT01793168, Sanford Health, observational, recruiting) [93], and the European clinical trials register (CTIS) had no records for MSS, SIL1, CCFDN or CTDP1. All therapeutic research in MSS is preclinical, in the woozy mouse:

i.p.: intraperitoneal; i.v.: intravenous; TAT: transduction peptide enabling cellular uptake of the protein produced in the liver.

These results do not allow comparison between studies, because they differ in timing of treatment (neonatal, 4 weeks, presymptomatic), route, outcome and duration, and none has human safety data. The negative study by Lavigna, with drugs already used in clinical practice and regimens active in other neurodegeneration models, shows that the repurposing of neuroprotective agents does not automatically translate to MSS [94]. Systemic AAV8 therapy corrected mainly the peripheral compartment, without SIL1 in the cerebellum, and peak expression in the quadriceps occurred 2 weeks after treatment, with a subsequent decline [10]; neonatal intracerebroventricular treatment corrected the cerebellum, but neonatal administration presupposes presymptomatic diagnosis [11]. L-serine has not been studied in patients [41].

Developments in the last 6–12 months (November 2025 to October 2026). Preclinical: systemic AAV8-SIL1-TAT gene therapy (Biochemical Pharmacology, published online 2 May 2026) [10]; cerebral AAV-PHP.eB-SIL1 gene therapy (bioRxiv, preprint of 20 September 2026) [11]; systematic phenotyping of the woozy mouse (December 2025) [36]. Descriptive human studies: systematic review of muscle imaging with two new cases [47]; new variants with functional or structural characterisation in Greece, Turkey and China [34, 49, 50]; dual pathology of MSS and dysferlinopathy [48]; review of conceptual therapies for CCFDN [69]. Guidelines: publication by ERN-RND, on 28 July 2026, of the NEUROGED guidelines on urinary and sexual symptoms for ataxias and spastic paraplegias [58]. There were no regulatory opinions or authorisations.

7.10. Anaesthesia, perioperative care and agents to avoid

The GeneReviews chapter on MSS has no section on anaesthesia or on agents to avoid [1]. Three anaesthetic reports have been published: a 1991 letter in The Lancet on malignant hyperthermia and MSS [95], a 1994 report of general anaesthesia [96] and a 2021 report on the anaesthesia of a child with MSS for cataract surgery [97]; none has an abstract, and their content was not read, so it is not possible to quantify the risk or describe the management. By inference, and not by source recommendation, the coexistence of myopathy, repeated ophthalmic and orthopaedic surgery and the mention of malignant hyperthermia in the title of the 1991 letter justify a prior anaesthetic assessment and communication of the diagnosis to the anaesthetic team. In CCFDN, general anaesthesia has been associated with pulmonary oedema, inspiratory stridor, malignant hyperthermia and seizures, without unequivocal documentation; cautious use and close postoperative monitoring, possibly in intensive care, are recommended [2, 62, 70]. With botulinum toxin, the labels warn of spread of the toxin effect (dysphagia, breathing difficulty) and the Portuguese SmPC states that safety under general anaesthesia or deep sedation has not been assessed [87, 92]. Abrupt withdrawal of baclofen may cause hallucinations and seizures, and that of tizanidine hypertension, tachycardia and rebound hypertonia, which matters during perioperative fasting periods [88, 91].

7.11. Pregnancy and lactation

The sources consulted do not describe pregnancies in women with MSS; a Europe PMC search on 26 October 2026 found no relevant reports, which does not demonstrate that none exist, and fertility in MSS has not been quantified. In CCFDN, three women had uneventful term pregnancies [2]. For the supportive drugs: baclofen should not be used in pregnancy unless the benefit outweighs the risk, postnatal withdrawal seizures have been reported in newborns exposed in utero, and it passes into breast milk in minute quantities with no expected reactions in the infant [86]; in the United States, teratogenicity (omphalocele) was described in rats at about 13 times the maximum human dose [88]; tizanidine should not be used in pregnancy unless there is clear benefit, nor during breastfeeding [90]; botulinum toxin should not be used in pregnancy or in women of childbearing potential not using contraception, unless clearly necessary, and is not recommended during breastfeeding [92]; Sustenon® is contraindicated in pregnancy [79].

7.12. Transition to adult care

Transfer to adult care is a change in care setting; the Endo-ERN guideline recommends transition plans and the move from pubertal induction to permanent adult hormone replacement at the end of induction [61]. In the North American GeneReviews model, transition begins in adolescence, with educational services up to 21 years of age [1]. In MSS, transition includes the move from paediatric neurology to adult neurology and physiatry, continuity of ophthalmological, orthopaedic and endocrine surveillance (section 11) and assessment of social and mobility support.

7.13. Applicable guidelines and divergences

EAN: European Academy of Neurology; EFAS: European Federation of Autonomic Societies; INUS: International Neuro-Urology Society. There is a relevant terminological divergence between the sources: the Japanese article describes the hypogonadism of MSS as hypogonadotrophic, whereas GeneReviews and the muscle imaging series describe it as hypergonadotrophic [1, 9, 47]; measurement of gonadotrophins before induction clarifies each patient's situation, and the Endo-ERN guideline covers both pituitary and gonadal deficiency [61].

8. Reproductive Options and Family Counselling

8.1. Inheritance and recurrence risks

MSS is autosomal recessive. The parents of an affected child are presumed to be heterozygous, and their status should be confirmed by molecular testing when the proband's diagnosis is molecular, to give a reliable estimate of the recurrence risk [1]. If both parents are heterozygous, each sibling has, at conception, a 25% chance of being affected, a 50% chance of being an asymptomatic carrier and a 25% chance of being neither affected nor a carrier; heterozygotes are not at risk of developing the disease [1]. Intrafamilial variability prevents prediction of severity in an affected sibling from the proband [1].

8.2. Carrier and relative testing

Carrier detection requires prior identification of the familial variants [1]. Testing should be considered for partners of known carriers and of affected people, especially when both have the same ancestry, as in the Finnish population, in which the carrier frequency is around 1:96 [1]. Asymptomatic at-risk siblings should be tested if the familial variants are known; if not, brain MRI or muscle biopsy may identify features of MSS and allow surveillance, especially ophthalmological, to be started [1]. In families without a molecular diagnosis, DNA banking from the proband allows future testing [1]. When the exome reveals a second diagnosis, such as concomitant dysferlinopathy, counselling must cover both genes [48]. In CCFDN, in endogamous Roma communities, carrier testing is recommended in the extended families of both parents and in future partners of carriers [2].

8.3. Prenatal diagnosis and preimplantation genetic testing

When the family's biallelic pathogenic variants have been identified, prenatal diagnosis and preimplantation genetic testing are possible [1]. In the Italian case in section 10, the second sibling was diagnosed with MSS during fetal life [47]. Professionals and families may have different perspectives on the use of prenatal and preimplantation diagnosis; most professionals consider it a personal decision, and discussion of these issues may be helpful [1]. The most appropriate time to discuss genetic risk and reproductive options is before pregnancy [1].

8.4. Counselling of young people and minors

Genetic counselling should be offered to young adults who are carriers or at risk of being carriers, including information on the risks to offspring and reproductive options [1]. Testing of asymptomatic minor siblings has direct benefit, because it allows ophthalmological and neurological surveillance to be started [1]; determination of carrier status, which has no medical benefit in childhood, becomes relevant at reproductive age, when GeneReviews recommends offering counselling [1]. Counselling should include information on the nature of the disease, inheritance and implications for the family, with construction of the pedigree [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

The prevalence of MSS is unknown [1]. The available figures measure different things and are not interchangeable:

The carrier frequency in Finland is about seven times the worldwide estimate, so a global figure underestimates the risk in the Finnish population [4]. Published case numbers measure the literature and not the frequency of the disease.

9.2. Founder populations and geographical distribution

In Finland, MSS is due to a founder variant (NM_022464.5:c.506_509dup), with a carrier frequency of about 1:96 [1]. In Japan, the variant c.936dup accounted for 43 of 48 alleles (89.6%) in the national cohort, and 31 of 32 chromosomes with this variant (96.9%) shared the same haplotype, versus 18 of 184 control chromosomes (9.8%), demonstrating a founder effect [9]. The same variant was found in Pakistani patients, and there are consanguineous Pakistani families with other variants at 5q31 [44, 99]. French-Canadian families with novel variants causing ataxia and cerebellar atrophy have been described [100], as has a large endogamous family (Superneau) studied by Ezgu and colleagues [51], and patients from Turkey, Greece, China, Uzbekistan and Italy (a family of Pakistani origin) in the 2025–2026 publications [34, 47–50]. Among the European series, Krieger and colleagues gathered 62 patients with ataxia, cataracts and myopathy, and Terracciano and colleagues studied 34 children with ataxia and cerebellar atrophy by muscle biopsy [35, 46]. In the United States, Reinker's orthopaedic series comes from Hawaii [57]. The distribution of variants reflects consanguinity and founder effects, and the test yield depends on these: it is higher in Japan (89%) than in European cohorts with a variable phenotype [9, 35].

CCFDN is exclusive to the Roma population, in particular the Vlax Roma; the carrier frequency is about 7% among the Rudari and 1.4–1.5% in the European Roma population in general [2, 30]. One in 10 European Roma carries one of four founder variants for neuromuscular disorders (NDRG1, CHRNE, CTDP1, SGCG), with marked differences between groups [30]. A door-to-door survey in Bulgaria, covering about 90% of the Roma population, identified 511 patients with neuromuscular disorders, with CCFDN among the most frequent [30].

9.3. Portugal and Brazil

The sources consulted contain no Portuguese or Brazilian MSS series. At the 125th ENMC workshop, the Portuguese data, collected by questionnaire sent to all paediatric neurologists and neurologists and to the molecular genetics department, showed that in the Iberian Gypsy population CCFDN had been demonstrated in several cases, together with the hereditary motor and sensory neuropathies of the Lom and Russe types (HMSN-Lom, HMSN-Russe), and that some Portuguese patients with Charcot-Marie-Tooth neuropathy had associated cerebellar ataxia [30]. The Brazilian contribution identified is historical: the article by Rodrigues and colleagues (2024), published in Arquivos de Neuro-Psiquiatria, on the eponym and the first description by Moravcsik [22]. The absence of data in the sources consulted does not demonstrate the absence of patients in these countries.

9.4. Special populations

In the Roma population, suspicion of CCFDN should precede that of MSS in the presence of congenital cataracts with microcornea, and galactokinase deficiency due to GALK1 NM_000154.2:c.82C>A p.(Pro28Thr) is the main differential in infancy [2]. In Finnish and Japanese families, targeted testing for the founder variant is an efficient first step [1, 9]. People with intellectual disability, visual impairment and reduced mobility need an adapted cognitive assessment, which should take into account visual impairment and schooling, as the GeneReviews chapter on CCFDN emphasises [2]. In children, hormonal formulations and antispasticity drugs are mostly adult formulations or have restricted paediatric indications (section 7.8).

9.5. European Reference Networks and patient organisations

MSS spans three European Reference Networks: ERN-RND (rare neurological diseases, ataxia and hereditary spastic paraplegia group), which provides the diagnostic flowcharts for ataxias and the NEUROGED guidelines [13]; EURO-NMD (rare neuromuscular diseases), for the myopathy and, in CCFDN, the neuropathy [14]; and ERN-EYE (rare eye diseases), for the cataracts [15]. Ataxia patient organisations include Euro-ATAXIA, the European federation [101], Ataxia UK [102], the National Ataxia Foundation in the United States [103], the Portuguese Association of Hereditary Ataxias (APAHE), founded in 2006 [104], and the Brazilian Association of Hereditary and Acquired Ataxias (ABAHE) [105]. MedlinePlus Genetics has summaries on MSS and CCFDN [2, 98].

10. Illustrative Clinical Case

10.1. Two siblings with MSS and muscle imaging (Buchignani and colleagues, 2026)

Buchignani and colleagues, in Pisa, described two siblings of Pakistani origin, children of consanguineous parents, aged 10 years and 22 months at the time of publication [47]. The older sister had appropriate developmental milestones up to 10 months, but independent walking was delayed; she was referred to paediatric neurology at 5 years for psychomotor delay and gait ataxia. At that time she had hypotonia, mild leg hypotrophy, hyporeflexia and cerebellar signs (ataxic gait, not yet independent, tremor, dysmetria and nystagmus), bilateral cataracts and short stature [47]. CK was 293 U/L and brain MRI showed hemispheric and predominantly vermian cerebellar atrophy, with cortico-subcortical hyperintensity on FLAIR (fluid-attenuated inversion recovery) sequences, thinning of the superior and middle cerebellar peduncles and mild pontine hypoplasia [47]. SIL1 testing revealed the homozygous variant described in the article as c.1276_1306del30 (p.Q426_L435del), whose normalised description is NM_022464.5:c.1276_1306del p.(Gln426SerfsTer22) (section 2.3) [33, 47].

After diagnosis, the patient had regular follow-up and surgery for bilateral cataracts. At 10 years she had generalised hypotonia, joint hyperlaxity, hyporeflexia, short stature, mildly reduced muscle trophism, mainly in the lower limbs, and weakness of the girdles and lower limbs; she still had an ataxic gait but walked independently without aids [47]. Brain MRI at 6 and 10 years showed stability [47]. MRI of the pelvis and lower limbs at 10 years showed mild to moderate fibro-fatty replacement of the gluteus maximus, medius and minimus and of the tensor fasciae latae, involvement of the posterior compartment of the thigh, in particular the adductor magnus and sartorius, diffuse infiltration of the leg except for the tibialis anterior and posterior, and hypotrophy of the gluteus maximus and tensor fasciae latae; clinically there was a Trendelenburg gait and conduction velocities were normal [47].

Her brother was diagnosed with MSS during fetal life, because of the family history [47]. He acquired head control at 6 months and, at 19 months, could not yet sit without support; he had axial hypotonia, joint hyperlaxity, hyporeflexia, poor antigravity movements, dysmetria, hypomimia and growth retardation, and did not yet have cataract [47]. Brain MRI confirmed cerebellar atrophy with cortico-subcortical hyperintensity similar to his sister's, and muscle MRI showed fibro-fatty degeneration with the same pattern [47]. Figure 2 of the article, which was consulted, presents the 3 T axial T1-weighted images of the pelvis, thigh and leg of the two siblings (Figure 2) [47].

10.2. Clinical interpretation of the case

The case brings together the elements of diagnosis and follow-up. Weakness and motor delay preceded the cataract in both siblings, and in the younger brother the cataract was still absent at 19 months, as described in the Krieger and Goto series [9, 35]. Cerebellar atrophy with cortical hyperintensity was already present in infancy [1, 47]. The sister acquired independent walking, in contrast with the Japanese series, in which no patient with SIL1 variants acquired it, showing the variability between populations and variants [9]. Muscle MRI detected involvement in an infant still without cataract, and the authors propose it as a biomarker of progression; this use is not validated and is not included in GeneReviews, which does not include muscle imaging in surveillance [1, 47]. Prenatal diagnosis in the second child corresponds to the option described in GeneReviews when the familial variants are known [1].

10.3. Complementary histopathology figure

Figure 1 of Goto and colleagues, which was consulted, shows on modified Gomori trichrome staining the rimmed vacuoles in the muscle of a patient with a SIL1 variant and their absence in a patient without a variant (20 μm scale bar) (Figure 1) [9].

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

Motor function worsens for some years and then stabilises, at an unpredictable age and degree; many patients never walk without support, many adults have severe disability and life expectancy appears to be near normal [1]. In the Japanese cohort (24 patients with SIL1 variants, observed between 2 and 52 years of age), no patient acquired independent walking, wheelchair dependence occurred between 13 and 28 years (mean 17.4 ± 6.3 years) and 5 of 16 lost walking with support between 13 and 28 years; there were no life-threatening events, and respiratory, cardiac and swallowing functions were preserved even beyond 50 years of age [9]. These data come from a cohort of 24 patients and do not demonstrate an absence of lifetime respiratory or cardiac risk. In Finnish adults, the myopathy is severe and progressive and proportional to disability [54]. In the muscle imaging review, 9 of 14 patients walked at some stage, and a 10-year-old child with independent walking had stable brain MRI between 6 and 10 years of age [47]. The visual prognosis depends on timely cataract surgery [9]. There are no data on treated disease that would allow comparison of the course with and without supportive interventions.

In the differential diagnoses, the prognosis is different. In CCFDN, the neuropathy leads to severe disability in the third decade, axonal loss determines disability, and episodes of rhabdomyolysis were associated with permanent loss of ambulation in 3 of 16 patients [2, 62]. In GBA2-related disease, progression leads to complete wheelchair dependence between the fifth and seventh decades [21].

11.2. Initial assessment after diagnosis

11.3. Surveillance

For the ataxias and spastic paraplegias, ERN-RND recommends asking regularly about urinary and sexual symptoms, urinalysis at initial assessment and in the event of worsening or infection, a 3-day bladder diary, post-void residual at baseline and with new symptoms, and baseline urea and creatinine; urodynamics is reserved for atypical symptoms, upper urinary tract risk or failure of conservative treatment; intermittent catheterisation is first line if the residual is consistently above 150 mL; antimuscarinics or β3 agonists treat storage symptoms, without routine antibiotic prophylaxis in those who catheterise; and phosphodiesterase 5 inhibitors treat erectile dysfunction, with testosterone measurement in the appropriate context [58]. These recommendations apply mainly to adults with MSS and to GBA2-related disease, which has urge incontinence; the GeneReviews chapter on MSS does not describe urinary symptoms [1, 21, 58]. Repeated muscle MRI and brain MRI were used in the follow-up of one case, without a validated interval [47].

11.4. At-risk relatives

Asymptomatic at-risk siblings should be assessed by molecular testing, if the familial variants are known, or by brain MRI or muscle biopsy, if they are not, so that surveillance can be started early [1]. In CCFDN, older and younger siblings should be assessed for early ophthalmological, neurological and endocrine treatment [2].

12. Summary and Final Considerations

Marinesco-Sjögren syndrome is an autosomal recessive disorder caused by biallelic loss of function of SIL1, the nucleotide exchange factor of the endoplasmic reticulum chaperone BiP, which disrupts protein quality control and affects mainly Purkinje cells and skeletal muscle [1, 16, 17]. The picture begins in infancy with hypotonia and motor delay, followed by cerebellar atrophy (100% of patients studied), rapidly developing bilateral cataracts (at a mean of 3.5 years), progressive vacuolar myopathy, intellectual disability (>90%, with normal intelligence possible), strabismus, short stature, hypergonadotrophic hypogonadism and skeletal anomalies [1, 9, 35]. Weakness precedes the cataract, so brain MRI, CK and muscle biopsy with electron microscopy may bring forward the diagnosis in the hypotonic child with cerebellar atrophy [9, 46].

Molecular diagnosis is made by sequencing and deletion analysis of SIL1, on a panel or exome, with targeted testing for the Finnish (c.506_509dup) and Japanese (c.936dup) founder variants when ancestry warrants it [1, 9]. About 40% of characteristic phenotypes have no SIL1 variant, and the detection rate is 60% with the complete triad and less than 3% with partial presentations, so a negative result requires a search for phenocopies [1, 35]. Among these, CCFDN due to CTDP1 c.863+389C>T, exclusive to the Roma population, is distinguished by congenital cataracts with microcornea, demyelinating neuropathy, parainfectious rhabdomyolysis and hypogonadotrophic hypogonadism, and requires targeted testing because the variant is deep intronic [2]; GBA2-related disease is distinguished by spasticity, axonal neuropathy and raised glucosylceramide [21]; INPP5K-related disease by the absence of ataxia and cerebellar atrophy [1, 31]; and cerebrotendinous xanthomatosis, which is treatable, by raised cholestanol [20].

Treatment is supportive and multidisciplinary: early cataract surgery, physiotherapy and occupational therapy, swallowing assessment, augmentative communication, educational support, orthopaedics and pubertal induction with hormone replacement at the expected age of puberty, following the model of the Endo-ERN guideline for primary hypogonadism, with doses and indications that in the European and North American labels are largely for adults [1, 61, 77, 79]. For anaesthesia in MSS there are only isolated reports, whose content was not read, and in CCFDN caution and postoperative monitoring are recommended [2, 95, 97]. There are no clinical trials in humans; AAV gene therapy prevented or delayed the disease in the woozy mouse, by the neonatal cerebral or systemic route, but remains preclinical, and the UPR-modulating drugs tested in the model were not effective [10, 11, 94]. Life expectancy appears to be near normal, with motor disability that stabilises after some years of worsening and wheelchair dependence in adolescence or early adulthood in many patients [1, 9]. Genetic counselling follows recessive inheritance, with attention to founder populations and to the possibility of prenatal and preimplantation diagnosis when the familial variants are known [1].

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