A novel de novo TMEM63A variant in a patient with severe hypomyelination and global developmental delay

BackgroundHeterozygous variants in TMEM63A have been recently identified as the cause of infantile-onset transient hypomyelination. To date, four TMEM63A variants have been reported in five patients. These patients exhibited favorable clinical course, developmental progress, and completion of myelination.Case reportThe patient was a 5-year-old girl with severe global developmental delay, absent speech, no turning over, no gazing, hypotonia, and daily episodes of autonomic seizures. Brain MRI showed hypomyelination of deep and subcortical white matter that appeared hyperintense in T2-weighted imaging from 2 months of age and that showed no change at 4 years of age. Exome sequencing of the patient and her parents revealed a novel de novo missense variant, NM_014698.3:c.1658G>T, p.(Gly553Val), in the TMEM63A gene, which was confirmed by Sanger sequencing. The variant has not been registered in public databases, and it substitutes a highly conserved glycine residue located in a pore-lining transmembrane helix. No other candidate variants were identified.ConclusionsAlthough TMEM63A variants are generally thought to cause transient hypomyelination with favorable developmental progress, identification of a de novo TMEM63A variant in our patient suggests that the TMEM63A-related clinical spectrum is broad and includes severe developmental delay with seizures.     

De novo POLR2A p.(Ile457Thr) variant associated with early-onset encephalopathy and cerebellar atrophy: expanding the phenotypic spectrum

BackgroundHeterozygous POLR2A variants have been recently reported in patients with a neurodevelopmental syndrome characterized by profound infantile-onset hypotonia. POLR2A encodes the highly conserved RBP1 protein, an essential subunit of the DNA-dependent RNA polymerase II.Case presentationWe investigated a 12-year-old girl presenting with an early-onset encephalopathy characterized by psychomotor delay, facial dysmorphism, refractory epilepsy with variable seizure types, behavioural abnormalities, and sleep disorder. Brain MRI showed a slowly progressive cerebellar atrophy. Trio-exome sequencing (Trio-ES) revealed the de novo germline variant NM_000937.5:c.1370T>C; p.(Ile457Thr) in POLR2A. This variant was previously reported in a subject with profound generalized hypotonia and muscular atrophy by Haijes et al. Our patient displayed instead a severe epileptic phenotype with refractory hypotonic seizures with impaired consciousness, myoclonic jerks, and drop attacks.ConclusionThis case expands the clinical spectrum of POLR2A-related syndrome, highlighting its phenotypic variability and supporting the relevance of epilepsy as a core feature of this emerging condition.     

Genetic analysis of the fused in sarcoma gene in Chinese Han patients with Parkinson's disease

Background and purposeExome sequencing in a large essential tremor (ET) family identified a novel nonsense mutation (p.Q290X) in the fused in sarcoma gene (FUS) as the cause of this family. Because of the clinical overlap between ET and Parkinson's disease (PD), the role of FUS in an independent cohort of PD patients from China mainland was evaluated.MethodsThe entire coding region of FUS in 508 Chinese Han patients with PD and the identified variants in 633 normal controls were evaluated. A variant was further screened in an additional 382 controls for the frequency in our population.ResultsA novel variant c.696C > T (p.Y232Y) in 2 sporadic patients with PD and six variants (c.52C > A, p.P18T; c.52C > T, p.P18S; c.147C > A, p.G49G; c.291C > T, p.Y97Y; c.684C > T, p.G228G; c.1176G > A, p.M392I) without significant difference in genotypic and allelic distributions in our PD cohort were identified.ConclusionThe FUS gene is not a genetic risk factor for PD in the population of Chinese Han ethnicity.     

A case of QARS1 associated epileptic encephalopathy and review of epilepsy in aminoacyl-tRNA synthetase disorders

IntroductionMutations in QARS1, which encodes human glutaminyl-tRNA synthetase, have been associated with epilepsy, developmental regression, progressive microcephaly and cerebral atrophy. Epilepsy caused by variants in QARS1 is usually drug-resistant and intractable. Childhood onset epilepsy is also reported in various aminoacyl-tRNA synthetase disorders. We describe a case with a milder neurological phenotype than previously reported with QARS1 variants and review the seizure associations with aminoacyl-tRNA synthetase disorders.Case reportThe patient is a 4-year-old girl presenting at 6 weeks of age with orofacial dyskinesia and hand stereotypies. She developed focal seizures at 7 months of age. Serial electroencephalograms showed shifting focality. Her seizures were controlled after introduction of carbamazepine. Progress MRI showed very mild cortical volume loss without myelination abnormalities or cerebellar atrophy. She was found to have novel compound heterozygous variants in QARS1 (NM_005051.2): c.[1132C > T];[1574G > A], p.[(Arg378Cys)];[(Arg525Gln)] originally classified as “variants of uncertain significance” and later upgraded to “likely pathogenic” based on functional testing and updated variant database review. Functional testing showed reduced solubility of the corresponding QARS1 mutants in vitro, but only mild two-fold loss in catalytic efficiency with the c.1132C > T variant and no noted change in tRNA^Gln aminoacylation with the c.1574G > A variant.ConclusionWe describe two QARS1 variants associated with overall conserved tRNA aminoacylation activity but characterized by significantly reduced QARS protein solubility, resulting in a milder clinical phenotype. 86% of previous patients reported with QARS1 had epilepsy and 79% were pharmaco-resistant. We also summarise literature regarding epilepsy in aminoacyl-tRNA synthetase disorders, which is also often early onset, severe and drug-refractory.     

Congenital myopathy and epidermolysis bullosa due to PLEC variant

We report on an adult Turkish patient with mild myopathy with a fiber-type disproportion and mitochondrial disorganization caused by genetic variants in the plectin gene (PLEC). Molecular genetic panel testing revealed two homozygous variants in PLEC (NM_000445.4): c.8306C>G (p.Pro2769Arg) and c.7506 + 5C>G (p. ?) that were classified as variants of unknown significance (class 3) following ACMG guidelines for variant classification in genetic diagnostics. A thorough reassessment of the patient revealed mild skin blistering (epidermolysis bullosa simplex, EBS). This illustrates the importance of deep phenotyping of neuromuscular patients.     

A novel splice site CUL3 variant in a patient with neurodevelopmental delay

BackgroundCUL3-related neurodevelopmental disorder is a recently described rare genetic condition characterized by global developmental delay and intellectual disability. Five affected individuals have been reported worldwide. The molecular and phenotypic spectrum of the disorder has yet to be fully elucidated. Splice variants in CUL3 are a well-described cause of pseudohypoaldosteronism type IIE; however, splice variants have not been associated with the neurodevelopmental disorder. We report the first individual with a neurodevelopmental disorder attributed to a CUL3 splice site variant.Case ReportThe patient presented with congenital developmental dysplasia of the hip and global developmental delay. A de novo splice site variant (c.379-2A > G) was identified in CUL3 and is predicted to abolish the acceptor splice site.ConclusionThis is the first report of an individual with a splice site variant causing CUL3-related neurodevelopmental disorder and expands our understanding of this rare condition.     

Recessive null-allele variants in MAG associated with spastic ataxia,nystagmus, neuropathy,and dystonia

IntroductionThe gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation.MethodsFour unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed.ResultsIn all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date.ConclusionsOur study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.     

Phenotypes of SMA patients retaining SMN1 with intragenic mutation

BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous deletion or intragenic mutation of the SMN1 gene. It is well-known that high copy number of its homologous gene, SMN2, modifies the phenotype of SMN1-deleted patients. However, in the patients with intragenic SMN1 mutation, the relationship between phenotype and SMN2 copy number remains unclear.MethodsWe have analyzed a total of 515 Japanese patients with SMA-like symptoms (delayed developmental milestones, respiratory failures, muscle weakness etc.) from 1996 to 2019. SMN1 and SMN2 copy numbers were determined by quantitative polymerase chain reaction (PCR) method and/or multiplex ligation-dependent probe amplification (MLPA) method. Intragenic SMN1 mutations were identified through DNA and RNA analysis of the fresh blood samples.ResultsA total of 241 patients were diagnosed as having SMA. The majority of SMA patients showed complete loss of SMN1 (n = 228, 95%), but some patients retained SMN1 and carried an intragenic mutation in the retaining SMN1 (n = 13, 5%). Ten different mutations were identified in these 13 patients, consisting of missense, nonsense, frameshift and splicing defect-causing mutations. The ten mutations were c.275G > C (p.Trp92Ser), c.819_820insT (p.Thr274Tyrfs*32), c.830A > G (p.Tyr277Cys), c.5C > T (p.Ala2Val), c.826 T > C (p.Tyr276His), c.79C > T (p.Gln27*), c.188C > A (p.Ser63*), c.422 T > C (p.Leu141Pro), c.835-2A > G (exon 7 skipping) and c.835-3C > A (exon 7 skipping). It should be noted here that some patients with milder phenotype carried only a single SMN2 copy (n = 3), while other patients with severe phenotype carried 3 SMN2 copies (n = 4).ConclusionIntragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers.     

Different patterns of cerebellar abnormality and hypomyelination between POLR3A and POLR3B mutations

Background

Mutations of POLR3A and POLR3B have been reported to cause several allelic hypomyelinating disorders, including hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome). Patients and methods: To clarify the difference in MRI between the two genotypes, we reviewed MRI in three patients with POLR3B mutations, and three with POLR3A mutations. Results: Though small cerebellar hemispheres and vermis are common MRI findings with both types of mutations, MRI in patients with POLR3B mutations revealed smaller cerebellar structures, especially vermis, than those in POLR3A mutations. MRI also showed milder hypomyelination in patients with POLR3B mutations than those with POLR3A mutations, which might explain milder clinical manifestations. Conclusions: MRI findings are distinct between patients with POLR3A and 3B mutations, and can provide important clues for the diagnosis, as these patients sometimes have no clinical symptoms suggesting 4H syndrome.     

Clinical Exome Sequencing Identifies a Novel TUBB4A Mutation in a Child With Static Hypomyelinating Leukodystrophy

BackgroundLeukodystrophies are a large group of inherited diseases of central nervous system myelin. There are few treatments, and most patients do not receive a final genetic diagnosis.PatientWe report a novel presentation of a female child with hypotonia, global developmental delay, and rotatory nystagmus. Brain MRI demonstrated profound hypomyelination and minimal or no atrophy in the brain stem or cerebellum.ResultsExtensive testing failed to yield a diagnosis until clinical whole-exome sequencing revealed a novel pathogenic mutation in the β-tubulin gene TUBB4A. TUBB4A is a cause of hereditary dystonia type 4 and has recently been reported to cause hypomyelination with atrophy of the basal ganglia and cerebellum.ConclusionsThis report expands the phenotypic spectrum of TUBB4A-associated neurological diseases to include static hypomyelinating leukodystrophy and supports the clinical relevance of next-generation sequencing diagnosis approaches.     

Phenotypes and Genotypes in Five Children with Congenital Insensitivity to Pain with Anhidrosis

BackgroundCongenital insensitivity to pain with anhidrosis is an extremely rare hereditary disorder linked to variants in NTRK1. Our goal was to characterize the clinical features and the genetic basis of the disorder in Chinese patients.MethodsPatients were enrolled via social networking. Clinical features were investigated by interview, chart review, and physical examination. DNA was extracted from peripheral blood to genotype NTRK1 in patients and their parents. Variants identified were checked against a control cohort by high-throughput sequencing, and the effects of these variants were assessed in silico.ResultsClinical features in five patients were cataloged, and six loss-of-function NTRK1 variants were identified, including a frameshift variant c.963delG, a nonsense variant c.1804C>T, an intron variant c.851-33T>A, and three missense variants c.1802T>G, c.2074C>T, and c.2311C>T.ConclusionsThe results expand the spectrum of clinical and genetic features of congenital insensitivity to pain with anhidrosis and will help facilitate analysis of genotype–phenotype association in the future.     

Genetic variants of methionine metabolism and X-ALD phenotype generation: results of a new study sample

X-linked adrenoleukodystrophy (X-ALD) is the most common inherited leukodystrophy. Nevertheless, no genotype–phenotype correlation has been established so far. Unidentified modifier genes or other cofactors are suspected to modulate phenotype and prognosis. We recently described polymorphisms of methionine metabolism as possible disease modifiers in X-ALD. To retest these findings, we analyzed 172 new DNA samples of X-ALD patients from different populations (France, Germany, USA, China) by genotyping eight genetic variants of methionine metabolism, including DHFR c.594+59del19bp, CBS c.844_855ins68, MTR c.2756A>G, MTHFR c.677C>T and c.1298A>C, MTRR c.60A>G, RFC1 c.80G>A, and Tc2 c.776C>G. We compared three X-ALD phenotypes: childhood-onset cerebral demyelinating inflammatory type (CCALD; n = 82), adulthood onset with focal cerebral demyelination (ACALD; n = 38), and adulthood onset without cerebral demyelination (AMN; n = 52). The association of genotypes and phenotypes was analyzed with univariate two-sided Pearson’s χ ². In the comparison between AMN and CCALD, the G allele of Tc2 c.776C>G was associated with X-ALD phenotypes (χ ² = 6.1; P = 0.048). The prevalence of the GG genotype of Tc2 c.776C>G was higher in patients with CNS demyelination compared to those without CNS demyelination (χ ² = 4.42; P = 0.036). The GG genotype was also more frequent in CCALD compared to AMN (χ ² = 4.7; P = 0.031). The other polymorphisms did not show any significant associations in this study sample. Whereas the influence of other polymorphisms of methionine metabolism was not confirmed, the present study supports the previously made observation that the Tc2 genotype contributes to X-ALD phenotype generation. Alexander Semmler and Xinhua Bao contributed equally to this work.     

Dopamine D3 receptor Ser9Gly variant is associated with impulse control disorders in Parkinson’s disease patients

IntroductionImpulse control disorders (ICD) are reported to occur at variable frequencies in different ethnic groups. Genetic vulnerability is suspected to underlie the individual risk for ICD. We investigated whether the allelic variants of dopamine (DRD3), glutamate (GRIN2B) and serotonin (HTR2A) receptors are linked to ICD in Indian Parkinson’s disease (PD) patients.MethodsWe conducted a prospective, case-control study which included PD patients (70 with ICD, 100 without ICD categorized after direct psychiatric interview of patient and caregiver) and 285 healthy controls. Single nucleotide polymorphism (SNP) variants of DRD3 p.S9G (rs6280), GRIN2B c.2664C>T (rs1806201) and HTR2A c.102T>C (rs6313) were genotyped.ResultsMultivariate regression analysis revealed that DRD3 p.Ser9Gly (rs6280) heterozygous variant CT (OR = 2.22, 95% CI: 1.03–4.86, p = 0.041), higher daily Levodopa equivalent doses (LED) of drugs (for 100 mg LED, OR = 1.14, 95% CI: 1.01–1.29, p = 0.041), current dopamine agonist but not Levodopa use (OR = 2.16, 95% CI: 1.03–4.55, p = 0.042) and age of onset of motor symptoms under 50 years (OR 2.09, 95% CI: 1.05–4.18, p = 0.035) were independently associated with ICD.ConclusionDRD3 p.Ser9Gly (rs6280) CT genotype is associated with ICD in Indian PD patients and this association is novel. Enhanced D3 receptor affinity due to gain-of-function conferred by the glycine residues could impair reward-risk assessment in the mesolimbic system and contribute to development of impulsive behaviour, in carriers of this genotype.     

Prevalent MLC1 mutation causing autosomal recessive megalencephalic leukoencephalopathy in consanguineous Palestinian families

BackgroundRecessive forms of megalencephalic leukoencephalopathy with subcortical cysts (MLC, OMIM 604004) is a rare early-onset leukodystrophy that presents with macrocephaly, seizures, slowly progressive gross motor deterioration, and MRI evidence of diffuse symmetric white matter swelling and subcortical cysts in the anterior temporal and frontoparietal regions. Later in the disease course, significant spasticity and ataxia develop, which may be accompanied by intellectual deterioration. This disease is caused mostly by biallelic pathogenic variants in the MLC1 gene.MethodsIn this study, we analysed the clinical and molecular architecture of 6 individuals, belonging to 4 unrelated consanguineous Palestinian families, presenting with consistent MLC features. We sequenced the entire coding and flanking intronic regions of the MLC1 gene.ResultsIn all recruited individuals, we detected one recurrent homozygous splice donor mutation NM_015166.4: c.423 + 1G > A. All parents were heterozygous carriers. The mutation abolishes a highly conserved splice site in humans and other species. In silico splice predictors suggested the loss of a canonical splice donor site (CADD score 33.0. SpliceAI: 0.980). The c.423 + 1G > A variant is rare; it was detected in only 4 heterozygous carriers in gnomAD.ConclusionIn this study, we identified a recurrent MLC1 variant (c.423 + 1G > A) as the cause of MLC among a group of Palestinian patients originating from a particular region of the country. Cost-effective studies should be performed to evaluate the implementation of carrier screening in adults originating from this region. Our findings have the potential to contribute to improved genetic diagnosis and carrier testing for individuals within this population and the wider community.     

Systematic TOR1A non-c.907_909delGAG variant analysis in isolated dystonia and controls

BackgroundAn increasing number of rare, functionally relevant non-c.907_909delGAG (non-ΔGAG) variants in TOR1A have been recognized, associated with phenotypic expressions different from classic DYT1 childhood-onset generalized dystonia. Only recently, DYT1 genotype-phenotype correlations have been proposed, awaiting further elucidation in independent cohorts.MethodsWe screened the entire coding sequence and the 5′-UTR region of TOR1A for rare non-ΔGAG sequence variants in a large series of 940 individuals with various forms of isolated dystonia as well as in 376 ancestry-matched controls. The frequency of rare, predicted deleterious non-ΔGAG TOR1A variants was assessed in the European sample of the Exome Aggregation Consortium (ExAC) dataset.ResultsIn the case cohort, we identified a rare 5′-UTR variant (c.-39G > T), a rare splice-region variant (c.445-8T > C), as well as one novel (p.Ile231Asn) and two rare (p.Ala163Val, p.Thr321Met) missense variants, each in a single patient with adult-onset focal/segmental isolated dystonia. Of these variants, only p.Thr321Met qualified as possibly disease-related according to variant interpretation criteria. One novel, predicted deleterious missense substitution (p.Asn208Ser) was detected in the control cohort. Among European ExAC individuals, the carrier rate of rare, predicted deleterious non-ΔGAG variants was 0.4%.ConclusionsOur study does not allow the establishment of genotype-specific clinical correlations for DYT1. Further large-scale genetic screening accompanied by comprehensive segregation and functional studies is required to conclusively define the contribution of TOR1A whole-gene variation to the pathogenesis of isolated dystonia.     

Atypical clinical course in two patients with GNB1 variants who developed acute encephalopathy

IntroductionVariants in the GNB1 gene, which encodes the β1 subunit of a trimeric G protein, can cause moderate to severe psychomotor retardation. Acute encephalopathies have also been observed in patients with central nervous system abnormalities; however, severe neurological sequelae have not previously been reported.Case presentationsPatient 1 was a Japanese female with a de novo GNB1 variant (c.284 T > C). At 8 months old she contracted influenza A and developed generalized convulsions. In the acute phase, brain magnetic resonance imaging (MRI) findings indicated acute encephalopathy; diffuse cerebral atrophy was present 1 month later. Although multidisciplinary treatment was administered, she had severe neurological sequelae including spastic tetraplegia, severe intellectual disabilities, and refractory epilepsy. Patient 2 was a Japanese male with a de novo GNB1 variant (c.239 T > C). He experienced an unexplained respiratory arrest aged 17 years; refractory convulsions developed. Brain MRI at 1 month showed bilateral basal ganglia high intensities; at 3 months, diffuse cerebral cortex and white matter atrophy was observed. Despite multidisciplinary treatment, he developed severe spastic tetraplegia and mental regression.DiscussionWe report two patients with GNB1 variants who had acute lesions on brain MRI and unexpected disease courses. In such patients with acute neurological deterioration, multidisciplinary treatment is required; patients should also be carefully observed for progression to acute encephalopathy.     

A novel INPP4A mutation with pontocerebellar hypoplasia,myoclonic epilepsy,microcephaly, and severe developmental delay

BackgroundThe inositol polyphosphate 4-phosphatase intracellular signaling pathway is susceptible to genetic or epigenetic alterations that may result in major neurological illnesses with clinically significant pons and cerebellum involvement.Case reportsA seven-year-old girl with pontocerebellar hypoplasia, resistant myoclonic epilepsy with axial hypotonia, microcephaly, atypical facial appearance, nystagmus, ophthalmoplegia, hyperactive tendon reflexes, spasticity, clonus, extensor plantar response, contractures in wrists and ankles and growth retardation, whole-exome sequencing was performed and a homozygous “NM_001134225.2:c.646C > T, p.(Arg216Ter)” variant was found in the INPP4A gene.ConclusionINPP4A mutations should be kept in mind in cases with severely delayed psychomotor development, progressive microcephaly, resistant myoclonic epilepsy, isolated cerebellum, and pons involvement.     

Étude rétrospective multicentrique de 15 cas adultes de xanthomatose cérébrotendineuse : aspects cliniques et paracliniques typiques et atypiques

IntroductionCerebrotendinous xanthomatosis, a metabolic leukodystrophy with an autosomal recessive inheritance, is secondary to deficiency of sterol 27-hydroxylase, an enzyme involved in cholesterol catabolism. Classical symptoms include clinical or infraclinical xanthomas affecting the skin and tendons, early cataracts, neurological signs and diarrhea. Brain imaging reveals involvement of the dentate nuclei and periventricular white matter hyperintensities. The diagnosis is based on an increased cholestanol level in serum, confirmed by the presence of a mutation in the CYP27A1 gene. Treatment is based on chenodeoxycholic acid.MethodWe report a retrospective multicentric study of 15 cases of cerebrotendinous xanthomatosis diagnosed in French adults. Clinical, molecular and MRI findings were recorded in all patients.ResultsThe average age at diagnosis was 39 years (range 27–65). Disease onset occurred in childhood in 73% of patients and in adulthood in 27%. All patients with a pediatric onset were diagnosed during adulthood (age range 28–65 years). Clinical symptoms variably associated cerebellar syndrome, pyramidal syndrome, cognitive decline, epilepsy, neuropathy (sought in 10 of our patients, present in forms in 8), psychiatric disorders, cataract and xanthomas. One patient had an atypical presentation: monoparesis associated with xanthomas. Brain MRI was abnormal in all: findings consisted in T2-weighted hyperintensity of the dentate nuclei (47%), periventricular leuoencephalopathy (73%) which preferentially involved the posterior cerebral part (60%), leucoencephalopathy with a vascular pattern (7%), hyperintensity of the cortico-spinal tracts (53%), globi pallidi, corpus callosum and cerebral atrophy (33%). Serum cholestanol was elevated in 93% of patients. The most frequent mutation was 1183C>T (n = 5/15). Under treatment with chenodeoxycholic acid, eight patients improved initially, followed by stabilization in five of them, and worsening in the others. Four patients died.ConclusionPatients with the xanthoma-neurological disorder association should be tested for cerebrotendinous xanthomatosis. The disease often begins in childhood with a diagnostic delay but also in adulthood. Involvement of the dentate nuclei is specific but not sensitive and the supratentorial leucoencephalopathy is not specific but with an antero-posterior gradient. A vascular distribution and involvement of the corpus callosum are possible. Serum cholestanol assay is very reliable: an elevated level provides the diagnosis, which must nevertheless be confirmed by molecular biology.     

Distal spinal muscular atrophy featured by predominant calf muscle involvement in VRK1 associated disease – Case series and review

We describe the shared clinical, biochemical, radiological and myopathological characteristics of four patients with distal spinal muscular atrophy (dSMA) caused by vaccinia-related kinase 1 (VRK1) variants and provide a review of the literature on phenotype-genotype correlations in VRK1-related disease. The clinical phenotype was characterized by adult-onset dSMA with predominant calf muscle involvement and mildly elevated serum creatinine kinase (CK) levels. Muscle imaging showed predominant atrophy and fatty replacement of calf muscles. We identified the novel compound heterozygous variants c.607C>T (p.Arg203Trp) and c.858G>T (p.Met286Ile) in two siblings with adult-onset dSMA. Additionally, two unrelated patients both carried the known c.583T>G (p.Leu195Val) VRK1 variant, with either c.197C>G (p.Ala66Gly) or c.701A>G (p.Asn234Ser) as a second variant. We conclude that compound heterozygous VRK1 variants cause distal spinal muscular atrophy with predominant posterior leg muscle involvement.