Deep phenotyping of the neuroimaging and skeletal features in KBG syndrome: a study of 53 patients and review of the literature.

BACKGROUND: KBG syndrome is caused by haploinsufficiency of ANKRD11 and is characterised by macrodontia of upper central incisors, distinctive facial features, short stature, skeletal anomalies, developmental delay, brain malformations and seizures. The central nervous system (CNS) and skeletal features remain poorly defined. METHODS: CNS and/or skeletal imaging were collected from molecularly confirmed individuals with KBG syndrome through an international network. We evaluated the original imaging and compared our results with data in the literature. RESULTS: We identified 53 individuals, 44 with CNS and 40 with skeletal imaging. Common CNS findings included incomplete hippocampal inversion and posterior fossa malformations; these were significantly more common than previously reported (63.4% and 65.9% vs 1.1% and 24.7%, respectively). Additional features included patulous internal auditory canal, never described before in KBG syndrome, and the recurrence of ventriculomegaly, encephalic cysts, empty sella and low-lying conus medullaris. We found no correlation between these structural anomalies and epilepsy or intellectual disability. Prevalent skeletal findings comprised abnormalities of the spine including scoliosis, coccygeal anomalies and cervical ribs. Hand X-rays revealed frequent abnormalities of carpal bone morphology and maturation, including a greater delay in ossification compared with metacarpal/phalanx bones. CONCLUSION: This cohort enabled us to describe the prevalence of very heterogeneous neuroradiological and skeletal anomalies in KBG syndrome. Knowledge of the spectrum of such anomalies will aid diagnostic accuracy, improve patient care and provide a reference for future research on the effects of ANKRD11 variants in skeletal and brain development.

De novo GRIN2A variants associated with epilepsy and autism and literature review.

N-methyl-D-aspartate receptors (NMDAR) are di- or tri-heterotetrameric ligand-gated ion channels composed of two obligate glycine-binding GluN1 subunits and two glutamate-binding GluN2 or GluN3 subunits, encoded by GRIN1, GRIN2A-D, and GRIN3A-B receptor genes respectively. Each NMDA receptor subtype has different temporal and spatial expression patterns in the brain and varies in the cell types and subcellular localization resulting in different functions. They play a crucial role in mediating the excitatory neurotransmission, but are also involved in neuronal development and synaptic plasticity, essential for learning, memory, and high cognitive functions. Among genes coding NMDAR subunits, GRIN2B is predominantly associated with neurodevelopmental disorders such as intellectual disability, developmental delay, autism, attention-deficit/hyperactivity disorder and, further, schizophrenia, Alzheimer's disease. The GRIN2A seems to be predominantly associated with a more definite phenotype including an epileptic spectrum ranging from Landau-Kleffner syndrome to benign childhood epilepsy with centrotemporal spikes, speech or language impairment, intellectual disability/developmental delay often in comorbidity. On the contrary, the occurrence of autism spectrum disorders, unlike GRIN2B-associated disorders, is questionable. To contribute to elucidate the latter issue and to better define the genotype/phenotype correlation, we report the clinical and neuropsychological profile of two patients featuring autism disorder, intellectual disability, language impairment, and focal epilepsy, associated with previously unreported heterozygous de novo GRIN2A pathogenic variants. We hypothesize that the unusual phenotype may be the result of interactions of tri-heterotetrameric 2GluN1/GluN2A-D/GluN3A-B subunits with mutated GluN2A subunit and/or the dysfunction may be influenced by other unknown modifier genes and/or environmental factors.

A Schematic Approach to Defining the Prevalence of COL VI Variants in Five Years of Next-Generation Sequencing.

OBJECTIVE: To define the prevalence of variants in collagen VI genes through a next-generation sequencing (NGS) approach in undiagnosed patients with suspected neuromuscular disease and to propose a diagnostic flowchart to assess the real pathogenicity of those variants. METHODS: In the past five years, we have collected clinical and molecular information on 512 patients with neuromuscular symptoms referred to our center. To pinpoint variants in COLVI genes and corroborate their real pathogenicity, we sketched a multistep flowchart, taking into consideration the bioinformatic weight of the gene variants, their correlation with clinical manifestations and possible effects on protein stability and expression. RESULTS: In Step I, we identified variants in COLVI-related genes in 48 patients, of which three were homozygous variants (Group 1). Then, we sorted variants according to their CADD score, clinical data and complementary studies (such as muscle and skin biopsy, study of expression of COLVI on fibroblast or muscle and muscle magnetic resonance). We finally assessed how potentially pathogenic variants (two biallelic and 12 monoallelic) destabilize COL6A1-A2-A3 subunits. Overall, 15 out of 512 patients were prioritized according to this pipeline. In seven of them, we confirmed reduced or absent immunocytochemical expression of collagen VI in cultured skin fibroblasts or in muscle tissue. CONCLUSIONS: In a real-world diagnostic scenario applied to heterogeneous neuromuscular conditions, a multistep integration of clinical and molecular data allowed the identification of about 3% of those patients harboring pathogenetic collagen VI variants.

12-Month progression of motor and functional outcomes in congenital myotonic dystrophy.

BACKGROUND: We aim to describe 12-mo functional and motor outcome performance in a cohort of participants with congenital myotonic dystrophy (CDM). METHODS: CDM participants performed the 6 Minute Walk Test (6MWT), 10 Meter Run, 4 Stair Climb, Grip Strength, and Lip Force at baseline and 12-mo visits. Parents completed the Vineland Adaptive Behavior Scale. RESULTS: Forty-seven participants, aged 0 to 13 y old, with CDM were enrolled. 6MWT, 10 Meter Run, and 4 Stair Climb were completed in >85% of eligible participants. The only significant difference between mean baseline and 12-mo performance was an improvement in 6MWT in children 3-6 y old (P = .008). This age group also had the largest mean % improvement in performance in all other timed functional testing. In children >7 y, the slope of change on timed functional tests decreased or plateaued, with further reductions in performance in children ≥10 y. Participants with CTG repeat lengths <500 did not perform differently than those with repeat lengths >1000. CONCLUSIONS: The 6MWT, 10 Meter Run, and 4 Stair Climb were the most feasible measures. Our findings are consistent with the clinical profile and prior cross-sectional data, helping to establish reasonable expectations of functional trajectories in this population as well as identifying points in which therapeutic interventions may be best studied. Further study of outcomes in children >10 y old and <3 y is warranted, but this new information will assist planning of clinical trials in the CDM population.

NGS in Hereditary Ataxia: When Rare Becomes Frequent.

The term hereditary ataxia (HA) refers to a heterogeneous group of neurological disorders with multiple genetic etiologies and a wide spectrum of ataxia-dominated phenotypes. Massive gene analysis in next-generation sequencing has entered the HA scenario, broadening our genetic and clinical knowledge of these conditions. In this study, we employed a targeted resequencing panel (TRP) in a large and highly heterogeneous cohort of 377 patients with a clinical diagnosis of HA, but no molecular diagnosis on routine genetic tests. We obtained a positive result (genetic diagnosis) in 33.2% of the patients, a rate significantly higher than those reported in similar studies employing TRP (average 19.4%), and in line with those performed using exome sequencing (ES, average 34.6%). Moreover, 15.6% of the patients had an uncertain molecular diagnosis. STUB1, PRKCG, and SPG7 were the most common causative genes. A comparison with published literature data showed that our panel would have identified 97% of the positive cases reported in previous TRP-based studies and 92% of those diagnosed by ES. Proper use of multigene panels, when combined with detailed phenotypic data, seems to be even more efficient than ES in clinical practice.

Genotype-phenotype correlations in recessive titinopathies.

PURPOSE: High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort. METHODS: We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families). RESULTS: Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364). CONCLUSION: Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.

Impaired Presynaptic High-Affinity Choline Transporter Causes a Congenital Myasthenic Syndrome with Episodic Apnea.

The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMSs), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.

Italian recommendations for diagnosis and management of congenital myasthenic syndromes.

Congenital myasthenic syndromes (CMS) are genetic disorders due to mutations in genes encoding proteins involved in the neuromuscular junction structure and function. CMS usually present in young children, but perinatal and adult onset has been reported. Clinical presentation is highly heterogeneous, ranging from mild symptoms to severe manifestations, sometimes with life-threatening respiratory episodes, especially in the first decade of life. Although considered rare, CMS are probably underestimated due to diagnostic difficulties. Because of the several therapeutic opportunities, CMS should be always considered in the differential diagnosis of neuromuscular disorders. The Italian Network on CMS proposes here recommendations for proper CMS diagnosis and management, aiming to guide clinicians in their practical approach to CMS patients.

CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56.

Hereditary spastic paraplegia (HSP) is an inherited disorder of the central nervous system mainly characterized by gradual spasticity and weakness of the lower limbs. SPG56 is a rare autosomal recessive early onset complicated form of HSP caused by mutations in CYP2U1. The CYP2U1 enzyme was shown to catalyze the hydroxylation of arachidonic acid. Here, we report two further SPG56 families carrying three novel CYP2U1 missense variants and the development of an in vitro biochemical assay to determine the pathogenicity of missense variants of uncertain clinical significance. We compared spectroscopic, enzymatic, and structural (from a 3D model) characteristics of the over expressed wild-type or mutated CYP2U1 in HEK293T cells. Our findings demonstrated that most of the tested missense variants in CYP2U1 were functionally inactive because of a loss of proper heme binding or destabilization of the protein structure. We also showed that functional data do not necessarily correlate with in silico predictions of variants pathogenicity, using different bioinformatic phenotype prediction tools. Our results therefore highlight the importance to use biological tools, such as the enzymatic test set up in this study, to evaluate the effects of newly identified variants in clinical settings.

Myoimaging in the NGS era: the discovery of a novel mutation in MYH7 in a family with distal myopathy and core-like features--a case report.

BACKGROUND: Myosin heavy chain 7 related myopathies are rare disorders characterized by a wide phenotypic spectrum and heterogeneous pathological features. In the present study, we performed clinical, morphological, genetic and imaging investigations in three relatives affected by autosomal dominant distal myopathy. Whilst earlier traditional Sanger investigations had pointed to the wrong gene as disease causative, next-generation sequencing allowed us to obtain the definitive molecular genetic diagnosis in the family. CASE PRESENTATION: The proposita, being found to harbor a novel heterozygous mutation in the RYR1 gene (p.Glu294Lys), was initially diagnosed with core myopathy. Subsequently, consideration of muscle magnetic resonance imaging (MRI) features and extension of family study led this diagnosis to be questioned. Use of next-generation sequencing analysis identified a novel mutation in the MYH7gene (p.Ser1435Pro) that segregated in the affected family members. CONCLUSIONS: This study identified a novel mutation in MYH7 in a family where the conclusive molecular diagnosis was reached through a complicated path. This case report might raise awareness, among clinicians, of the need to interpret NGS data in combination with muscle MRI patterns so as to facilitate the pinpointing of the main molecular etiology in inherited muscle disorders.

Longitudinal follow up of a boy affected by Pol III-related leukodystrophy: a detailed phenotype description.

BACKGROUND: The 4H syndrome (hypomyelination, hypodontia, hypogonadotropic hypogonadism) is a newly recognized leukodystrophy. The classical form is characterized by the association of hypomyelination, abnormal dentition, and hypogonadotropic hypogonadism, but the recent identification of two genes (POLR3A and POLR3B) responsible for the syndrome demonstrates that these three main characteristics can be variably combined among "Pol-III (polymerase III)-related leukodystrophies." CASE PRESENTATION: We report on the clinical, neuroradiological and endocrinological follow-up of a male affected by 4H syndrome with confirmed POLR3B mutations (c.1568 T > A/p.V523E variant in exon 15 and the novel c.1988C > T/p.T663I mutation in exon 19). Spastic-ataxic gait with worsening of motor performance, progressive moderate intellectual disability and language difficulties were the main neurological findings observed. The first six years of substantial stability of the clinical and imaging features were followed by additional six years that showed a progressive worsening of motor, language and learning disabilities in relation to a progression of the cerebellar involvement. Hypogonadotropic hypogonadism and growth hormone deficiency followed by central hypocortisolism became part of the patient's phenotype. Thyroid function resulted unaffected during follow up. CONCLUSIONS: A novel mutation in POLR3B in a patient with an analogue phenotype than those previously described but with more extensive endocrinological features, including hypogonadotropic hypogonadism, growth hormone deficiency and hypocortisolism, was described. These findings permit to better define the clinical spectrum of the disease, to direct specific genetic tests and to tailor clinical management.

Burden, professional support, and social network in families of children and young adults with muscular dystrophies.

INTRODUCTION: This study explores burden and social and professional support in families of young patients with muscular dystrophies (MDs) in Italy. METHODS: The study was carried out on 502 key relatives of 4- to 25-year-old patients suffering from Duchenne, Becker, or Limb-Girdle MD who were living with at least 1 adult relative. RESULTS: A total of 77.1% of relatives reported feelings of loss, 74.0% had feelings of sadness, and 59.1% had constraints in leisure activities. Burden was higher among relatives of patients with higher disability and who spent more daily hours in caregiving. Practical difficulties were higher among relatives who perceived lower help in patient emergencies and less practical support by their social network. Psychological burden was higher in those relatives who were unemployed, those with poorer support in emergencies, and those with lower social contacts. CONCLUSIONS: Caring for patients with MDs may be demanding for relatives even in the early stages of these disorders, especially when social support is poor and the patient's disability increases.

Novel dynein DYNC1H1 neck and motor domain mutations link distal spinal muscular atrophy and abnormal cortical development.

DYNC1H1 encodes the heavy chain of cytoplasmic dynein 1, a motor protein complex implicated in retrograde axonal transport, neuronal migration, and other intracellular motility functions. Mutations in DYNC1H1 have been described in autosomal-dominant Charcot-Marie-Tooth type 2 and in families with distal spinal muscular atrophy (SMA) predominantly affecting the legs (SMA-LED). Recently, defects of cytoplasmic dynein 1 were also associated with a form of mental retardation and neuronal migration disorders. Here, we describe two unrelated patients presenting a combined phenotype of congenital motor neuron disease associated with focal areas of cortical malformation. In each patient, we identified a novel de novo mutation in DYNC1H1: c.3581A>G (p.Gln1194Arg) in one case and c.9142G>A (p.Glu3048Lys) in the other. The mutations lie in different domains of the dynein heavy chain, and are deleterious to protein function as indicated by assays for Golgi recovery after nocodazole washout in patient fibroblasts. Our results expand the set of pathological mutations in DYNC1H1, reinforce the role of cytoplasmic dynein in disorders of neuronal migration, and provide evidence for a syndrome including spinal nerve degeneration and brain developmental problems.

Psychological and practical difficulties among parents and healthy siblings of children with Duchenne vs. Becker muscular dystrophy: an Italian comparative study.

This study explored the burden in parents and healthy siblings of 4-17 year-old patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies, and whether the burden varied according to clinical aspects and social resources. Data on socio-demographic characteristics, patient's clinical history, parent and healthy children burden, and on parent's social resources were collected using self-reported questionnaires administered to 336 parents of patients with DMD (246) and BMD (90). Parents of patients with DMD reported higher burden than those of patients with BMD, especially concerning feeling of loss (84.3% DMD vs. 57.4% BMD), stigma (44.2% DMD vs. 5.5% BMD) and neglect of hobbies (69.0% DMD vs. 32.5% BMD). Despite the burden, 66% DMD and 62.4% BMD parents stated the caregiving experience had a positive impact on their lives. A minority of parents believed MD has a negative influence on the psychological well-being (31.0% DMD vs. 12.8% BMD), and social life of unaffected children (25.7% vs. 18.4%). In the DMD group, burden correlated with duration of illness and parent age, and burden was higher among parents with lower social contacts and support in emergencies. In DMD, difficulties among healthy children were reported as higher by parents who were older, had higher burden and lower social contacts. In both groups, burden increased in relation to patient disability. These findings underline that the psychological support to be provided to parents of patients with MD, should take into account clinical features of the disease.

KLHL40-Related Myopathy: A Systematic Review and Insight into a Follow-up Biomarker via a New Case Report.

BACKGROUND: Mutations in the KLHL40 gene are a common cause of severe or even lethal nemaline myopathy. Some cases with mild forms have been described, although the cases are still anecdotal. The aim of this paper was to systematically review the cases described in the literature and to describe a 12-year clinical and imaging follow-up in an Italian patient with KLHL40- related myopathy in order to suggest possible follow-up measurements. METHODS: Having searched through three electronic databases (PubMed, Scopus, and EBSCO), 18 articles describing 65 patients with homozygous or compound heterozygous KLHL40 mutations were selected. A patient with a KLHL40 homozygous mutation (c.1582G>A/p.E528K) was added and clinical and genetic data were collected. RESULTS: The most common mutation identified in our systematic review was the (c.1516A>C) followed by the (c.1582G>A). In our review, 60% percent of the patients died within the first 4 years of life. Clinical features were similar across the sample. Unfortunately, however, there is no record of the natural history data in the surviving patients. The 12-year follow-up of our patient revealed a slow improvement in her clinical course, identifying muscle MRI as the only possible marker of disease progression. CONCLUSIONS: Due to its clinical and genotype homogeneity, KLHL40-related myopathy may be a condition that would greatly benefit from the development of new gene therapies; muscle MRI could be a good biomarker to monitor disease progression.

Characterization of Phenotypic Variability in Becker Muscular Dystrophy for Clinical Practice and Towards Trial Readiness: A Two-Years Follow up Study.

Background: Becker muscular dystrophy (BMD) is a dystrophinopathy due to in-frame mutations in the dystrophin gene (DMD) which determines a reduction of dystrophin at muscle level. BMD has a wide spectrum of clinical variability with different degrees of disability. Studies of natural history are needed also in view of up-coming clinical trials. Objectives: From an initial cohort of 32 BMD adult subjects, we present a detailed phenotypic characterization of 28 patients, then providing a description of their clinical natural history over the course of 12 months for 18 and 24 months for 13 of them. Methods: Each patient has been genetically characterized. Baseline, and 1-year and 2 years assessments included North Star Ambulatory Assessment (NSAA), timed function tests (time to climb and descend four stairs), 6-minute walk test (6MWT), Walton and Gardner-Medwin Scale and Medical Research Council (MRC) scale. Muscle magnetic resonance imaging (MRI) was acquired at baseline and in a subgroup of 9 patients after 24 months. Data on cardiac function (electrocardiogram, echocardiogram, and cardiac MRI) were also collected. Results and conclusions: Among the clinical heterogeneity, a more severe involvement is often observed in patients with 45-X del, with a disease progression over two years. The 6MWT appears sensitive to detect modification from baseline during follow up while no variation was observed by MRC testing. Muscle MRI of the lower limbs correlates with clinical parameters.Our study further highlights how the phenotypic variability of BMD adult patients makes it difficult to describe an uniform course and substantiates the need to identify predictive parameters and biomarkers to stratify patients.

The IAAM LTBP4 Haplotype is Protective Against Dystrophin-Deficient Cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is a major complication of, and leading cause of mortality in Duchenne muscular dystrophy (DMD). Its severity, age at onset, and rate of progression display wide variability, whose molecular bases have been scarcely elucidated. Potential DCM-modifying factors include glucocorticoid (GC) and cardiological treatments, DMD mutation type and location, and variants in other genes. Methods and Results: We retrospectively collected 3138 echocardiographic measurements of left ventricular ejection fraction (EF), shortening fraction (SF), and end-diastolic volume (EDV) from 819 DMD participants, 541 from an Italian multicentric cohort and 278 from the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS). Using generalized estimating equation (GEE) models, we estimated the yearly rate of decrease of EF (-0.80%) and SF (-0.41%), while EDV increase was not significantly associated with age. Utilizing a multivariate generalized estimating equation (GEE) model we observed that mutations preserving the expression of the C-terminal Dp71 isoform of dystrophin were correlated with decreased EDV (-11.01 mL/m2, p = 0.03) while for dp116 were correlated with decreased EF (-4.14%, p = <0.001). The rs10880 genotype in the LTBP4 gene, previously shown to prolong ambulation, was also associated with increased EF and decreased EDV (+3.29%, p = 0.002, and -10.62 mL/m2, p = 0.008) with a recessive model. Conclusions: We quantitatively describe the progression of systolic dysfunction progression in DMD, confirm the effect of distal dystrophin isoform expression on the dystrophin-deficient heart, and identify a strong effect of LTBP4 genotype of DCM in DMD.

Subclinical myopathy in a child with neutral lipid storage disease and mutations in the PNPLA2 gene.

We report a 14-year-old-boy with markedly elevated serum creatine kinase (CK) levels, in whom massive triglyceride storage was found in peripheral blood leukocytes and in muscle biopsy. Sequencing PNPLA2, the gene encoding the adipose triglyceride lipase (ATGL) and responsible for the neutral lipid storage disease with myopathy (NLSDM), we identified two heterozygous mutations, including a previously reported nonsense and a novel missense mutation in the patatin domain of the gene. Lipid storage myopathy can be clinically silent in childhood and presenting only with hyperCKemia.

Congenital Myopathy as a Phenotypic Expression of CACNA1S Gene Mutation: Case Report and Systematic Review of the Literature.

BACKGROUND: Congenital myopathies are a group of clinically, genetically, and histologically heterogeneous diseases caused by mutations in a large group of genes. One of these is CACNA1S, which is recognized as the cause of Dihydropyridine Receptor Congenital Myopathy. METHODS: To better characterize the phenotypic spectrum of CACNA1S myopathy, we conducted a systematic review of cases in the literature through three electronic databases following the PRISMA guidelines. We selected nine articles describing 23 patients with heterozygous, homozygous, or compound heterozygous mutations in CACNA1S and we added one patient with a compound heterozygous mutation in CACNA1S (c.1394-2A>G; c.1724T>C, p.L575P) followed at our Institute. We collected clinical and genetic data, muscle biopsies, and muscle MRIs when available. RESULTS: The phenotype of this myopathy is heterogeneous, ranging from more severe forms with a lethal early onset and mild-moderate forms with a better clinical course. CONCLUSIONS: Our patient presented a phenotype compatible with the mild-moderate form, although she presented peculiar features such as a short stature, myopia, mild sensorineural hearing loss, psychiatric symptoms, and posterior-anterior impairment gradient on thigh muscle MRI.

Case report: Episodic ataxia without ataxia?

Hereditary myopathies represent a clinically and genetically heterogeneous group of neuromuscular disorders, characterized by highly variable clinical presentations and frequently overlapping phenotypes with other neuromuscular disorders, likely influenced by genetic and environmental modifiers. Genetic testing is often challenging due to ambiguous clinical diagnosis. Here, we present the case of a family with clinical and Electromyography (EMG) features resembling a myotonia-like disorder in which Whole Exome Sequencing (WES) analysis revealed the co-segregation of two rare missense variants in UBR4 and HSPG2, genes previously associated with episodic ataxia 8 (EA8). A review of the literature highlighted a striking overlap between the clinical and the molecular features of our family and the previously described episodic ataxias (EAs), which raises concerns about the genotype-phenotype correlation, clinical variability, and the confounding overlap in these groups of disorders. This emphasizes the importance of thoroughly framing the patient's phenotype. The more clear-cut the diagnosis, the easier the identification of a genetic determinant, and the better the prognosis and the treatment of patients.