Progressive Limb-girdle Weakness Research Articles

High-risk screening for late-onset Pompe disease in China: An expanded multicenter study.

Late-onset Pompe disease (LOPD) is caused by a genetic deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA), leading to progressive limb-girdle weakness and respiratory impairment. The insidious onset of non-specific early symptoms often prohibits timely diagnosis. This study aimed to validate the high-risk screening criteria for LOPD in the Chinese population. A total of 726 patients were included, including 96 patients under 14 years of age. Dried blood spots (DBS) and tandem mass spectrometry (MS/MS) were employed to evaluate serum GAA activity. Forty-four patients exhibited a decreased GAA activity, 16 (2.2%) of which were confirmed as LOPD by genetic testing. Three previously unreported GAA mutations were also identified. The median diagnostic delay was shortened to 3 years, which excelled the previous retrospective studies. At diagnosis, most patients exhibited impaired respiratory function and/or limb-girdle weakness. Elevated serum creatine kinase (CK) levels were more frequently observed in patients who manifested before age 16. Overall, high-risk screening is a feasible and efficient method to identify LOPD patients at an early stage. Patients over 1 year of age with either weakness in axial and/or proximal limb muscles, or unexplained respiratory distress shall be subject to GAA enzymatic test, while CK levels above 2 times the upper normal limit shall be an additional criterion for patients under 16. This modified high-risk screening criteria for LOPD requires further validation in larger Chinese cohorts.

Early onset LGMDR19 with unusual features related to GMPPB gene in South Indian siblings with variable phenotype

Guanosine diphosphate mannose (GDP-mannose) pyrophosphorylase B (GMPPB) is a cytoplasmic enzyme that catalyzes the synthesis of GDP-mannose, a crucial substrate for several glycosylation pathways. Reports of pathogenic variants in the GMPPB gene are infrequent. As of April 2023, 109 cases with pathogenic variants in the GMPPB gene have been reported worldwide. Here, we present two siblings born of consanguineous parentage from Southern India. This is a retrospective study on genetically confirmed siblings with GMPPB pathogenic variants. The siblings, a 15-year-old girl, and a 13-year-old boy, presented with progressive limb-girdle weakness and cataracts from early childhood. The girl had exertion-induced breathlessness and mental subnormality. Creatine kinase levels were 5750 and 4320 IU/L. An echocardiogram of the heart revealed global hypokinesia, moderate left ventricular dysfunction, and mild mitral regurgitation with dilation of the left atrium and left ventricle in the girl child. Exome sequencing showed a homozygous pathogenic variant (NM_021971.4 (GMPPB): c.358A>G (p.Met120Val) in Exon 4 of GMPPB gene in both the siblings. Thus, we report an unusual early onset LGMD phenotype of GMPPB-related disorder with cardiac involvement and cataracts from a single family.

Frameshift mutation in SQSTM1 causes proximal myopathy with rimmed vacuoles: A case report.

p62/Sequestosome-1 (SQSTM1) is a stress-inducible scaffold protein involved in multiple cellular processes, including apoptosis, inflammation, cell survival, and selective autophagy. SQSTM1 mutations are associated with a spectrum of multisystem proteinopathy, including Paget disease of the bone, amyotrophic lateral sclerosis, frontotemporal dementia, and distal myopathy with rimmed vacuoles (MRV). Herein, we report a new phenotype of SQSTM1-associated proteinopathy, a novel frameshift mutation in SQSTM1 causing proximal MRV. A 44-year-old Chinese patient presented with progressive limb-girdle weakness. She had asymmetric proximal limb weakness and myopathic features on electromyography. The magnetic resonance images showed fatty infiltration into muscles, predominantly in the thighs and medial gastrocnemius, sparing the tibialis anterior. Muscle histopathology revealed abnormal protein deposition, p62/SQSTM1-positive inclusions, and rimmed vacuoles. Next-generation sequencing showed a novel pathogenic SQSTM1 frameshift mutation, c.542_549delACAGCCGC (p. H181Lfs*66). We expanded the pathogenic genotype of SQSTM1 to include a new, related phenotype: proximal MRV. We suggest that SQSTM1 variations should be screened in cases of proximal MRV.

GFPT1-Associated Congenital Myasthenic Syndrome Mimicking a Glycogen Storage Disease - Diagnostic Pitfalls in Myopathology Solved by Next-Generation-Sequencing.

GFPT1-related congenital myasthenic syndrome (CMS) is characterized by progressive limb girdle weakness, and less prominent involvement of facial, bulbar, or respiratory muscles. While tubular aggregates in muscle biopsy are considered highly indicative in GFPT1-associated CMS, excessive glycogen storage has not been described. Here, we report on three affected siblings with limb-girdle myasthenia due to biallelic pathogenic variants in GFPT1: the previously reported missense variant c.41G > A (p.Arg14Gln) and the novel truncating variant c.1265_1268del (p.Phe422TrpfsTer26). Patients showed progressive proximal atrophic muscular weakness with respiratory involvement, and a lethal disease course in adulthood. In the diagnostic workup at that time, muscle biopsy suggested a glycogen storage disease. Initially, Pompe disease was suspected. However, enzymatic activity of acid alpha-glucosidase was normal, and gene panel analysis including 38 genes associated with limb-girdle weakness (GAA included) remained unevocative. Hence, a non-specified glycogen storage myopathy was diagnosed. A decade later, the diagnosis of GFPT1-related CMS was established by genome sequencing. Myopathological reexamination showed pronounced glycogen accumulations, that were exclusively found in denervated muscle fibers. Only single fibers showed very small tubular aggregates, identified in evaluation of serial sections. This family demonstrates how diagnostic pitfalls can be addressed by an integrative approach including broad genetic analysis and re-evaluation of clinical as well as myopathological findings.

A.3 A novel recessive TNNT1 congenital core-rod myopathy in French Canadians

Background: Mutations in the slow skeletal muscle troponin T (TNNT1) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic testing. TNNT1 expression in muscle was assessed by quantitative PCR and immunoblotting. Wild type or mutated TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess for rescue of the morphant phenotype. Results: Four patients shared a novel missense homozygous mutation in TNNT1. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of rhabdomyolysis. Older patients remained ambulatory into their sixties. Lower extremity MRI showed symmetrical myopathic changes. Paraspinal MRI showed diffuse fibro-fatty involution. Biopsies showed multi-minicores. Nemaline rods were seen in half the patients. TNNT1 mRNA expression was similar in controls and patients, while levels of TNNT1 protein were reduced in patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to do so. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel mutation.

A.4 A Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians

Background: Mutations in the slow skeletal muscle troponin T (TNNT1) gene cause a congenital nemaline myopathy resulting in death from respiratory insufficiency in early infancy. We report on four French Canadians with a novel congenital TNNT1 myopathy. Methods: Patients underwent lower extremity and paraspinal MRI, quadriceps biopsy and genetic testing. TNNT1 expression in muscle was assessed by quantitative PCR and immunoblotting. Wild type or mutated TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess for rescue of the morphant phenotype. Results: Four patients shared a novel missense homozygous mutation in TNNT1. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of rhabdomyolysis. Older patients remained ambulatory into their sixties. Lower extremity MRI showed symmetrical myopathic changes. Paraspinal MRI showed diffuse fibro-fatty involution. Biopsies showed multi-minicores. Nemaline rods were seen in half the patients. TNNT1 mRNA expression was similar in controls and patients, while levels of TNNT1 protein were reduced in patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to do so. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel mutation.

High prevalence of sporadic late-onset nemaline myopathy in a cohort of whole-exome sequencing negative myopathy patients

Sporadic late-onset nemaline myopathy (SLONM) is an enigmatic, supposedly very rare, putatively immune-mediated late-onset myopathy, typically presenting with subacutely progressive limb-girdle muscular weakness, yet slowly progressing cases have been described too. We systematically studied (para)clinical and histopathological findings in a cohort of 18 isolated yet suspected inherited myopathy patients, showing late-onset, slowly progressive limb-girdle muscle weakness, remaining unsolved after whole-exome sequencing. The presence of a monoclonal gammopathy of unknown significance (MGUS) and anti-HMGCR antibodies was determined. Biopsies were systematically re-evaluated and systematic immunohistochemical and electron microscopy studies were performed to particularly evaluate the presence of rods and/or inflammatory features. Ten patients showed rods as core feature on muscle biopsy on re-evaluation, four of these had an IgG κ MGUS in blood. As such, these ten patients represented suspected slowly progressing SLONM patients, with auxiliary data supporting this diagnosis: 1) additional muscle biopsy features pointing towards Z-disk and myofibrillar pathology; 2) a common selective pattern of muscle involvement on MRI; 3) inflammatory features on muscle biopsy. Findings in this proof-of-concept study highlight difficulties in reliably diagnosing slowly progressing SLONM and the probably underestimated prevalence of this entity in cohorts of whole exome sequencing negative myopathy patients, initially considered having an inherited myopathy.

Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians.

Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on 4 French Canadians with a novel form of recessive congenital TNNT1 core-rod myopathy. Patients underwent full clinical characterization, lower limb magnetic resonance imaging (MRI), muscle biopsy, and genetic testing. A zebrafish loss-of-function model using morpholinos was created to assess the pathogenicity of the identified variant. Wild-type or mutated human TNNT1 mRNAs were coinjected with morpholinos to assess their abilities to rescue the morphant phenotype. Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). They developed from childhood very slowly progressive limb-girdle weakness with rigid spine and disabling contractures. They suffered from restrictive lung disease requiring noninvasive mechanical ventilation in 3 patients, as well as recurrent episodes of rhabdomyolysis triggered by infections, which were relieved by dantrolene in 1 patient. Older patients remained ambulatory into their 60s. MRI of the leg muscles showed fibrofatty infiltration predominating in the posterior thigh and the deep posterior leg compartments. Muscle biopsies showed multiminicores and lobulated fibers, rods in half the patients, and no fiber type disproportion. Wild-type TNNT1 mRNA rescued the zebrafish morphants, but mutant transcripts failed to do so. This study expands the phenotypic spectrum of TNNT1 myopathy and provides functional evidence for the pathogenicity of the newly identified missense mutation. ANN NEUROL 2020;87:568-583.

P.028 A milder congenital myopathy in the french canadians caused by a novel TNNT1 homozygous missense mutation

Background: Mutations of the slow skeletal muscle troponin-T1 (TNNT1) gene are a rare cause of nemaline myopathy. The phenotype is characterized by severe amyotrophy and contractures. Death from respiratory insufficiency occurs in infancy. We report on four French Canadians with a novel congenital TNNT1-related myopathy. Methods: Patients underwent MRI of leg muscles, quadriceps biopsy and genetic testing. Wild type or mutated human TNNT1 mRNAs were co-injected with morpholinos in a zebrafish knockdown model to assess their relative abilities to rescue the morphant phenotype. Results: Three adults and one child shared a novel missense homozygous pathogenic variant in the TNNT1 gene. They developed from childhood slowly progressive limb-girdle weakness with spinal rigidity and contractures. They suffered from restrictive lung disease and recurrent episodes of infection-triggered rhabdomyolysis, which were relieved by dantrolene in one patient. Older patients remained ambulatory into their sixties. MRI of leg muscles showed symmetrical atrophy and fatty infiltration in a proximal-to-distal gradient. Biopsies showed multi-minicores, while nemaline rods were seen in half the patients. Wild type TNNT1 mRNA rescued the zebrafish morphants but mutant transcripts failed to rescue the morphants. Conclusions: This study expands the spectrum of TNNT1-related myopathy to include a milder clinical phenotype caused by a functionally-confirmed novel missense mutation.

P.349 - Myofibrillar myopathies with autophagic vacuoles: Report of a case series

The presence of autophagic vacuoles containing lysosomal, autophagosomal and sarcolemmal membrane components depicts autophagic vacuolar myopathies as a spectrum of disorders unified by distinctive myopathologic features. While not being classified as autophagic vacuolar myopathies, also muscle disorders including myopathies with rimmed vacuoles, inclusion body myopathies and myofibrillar myopathies (MFM) have autophagic pathology. Here, we present the diagnostic algorithm which led us to the diagnosis of MFM in four unrelated patients with autophagic vacuolar myopathies. Patient 1 is a 39-year-old male, that came to our attention at the age of 35 for hyperCKemia (5× normal value) and a mild exercise intolerance; his clinical conditions have worsened in the last years of follow up, with the appearance of a progressive limb girdle weakness resembling a LGMD-like phenotype. Patient 2 is a 74-year-old woman with a 7-year history of a progressive axial and pelvic girdle weakness, in association with a moderate increase of blood CK (4× normal value). Patients 3 and 4 are respectively 19-year-old and 37-year-old males that present an asymptomatic hyperckemia (5× normal value), without muscle weakness. None of them is affected by cardiomyopathy. Their family history is inconsistent for neuromuscular diseases. The ultrastructural studies of the muscle biopsies have showed myofibrillar myopathy features, including progressive myofibrillar degeneration commencing at the Z-disk, accumulation of degraded filamentous material and entrapment of dislocated membranous organelles in autophagic vacuoles.

Limb girdle weakness responding to salbutamol: an Indian family with DOK7 mutation.

Congenital Myasthenic Syndromes (CMS) are heterogeneous genetic diseases. Two siblings presented with progressive limb girdle weakness without significant fluctuations or ocular muscle weakness. Repetitive nerve stimulation showed a decremental response and there was no response to pyridostigmine therapy. A trial of salbutamol produced a remarkable, consistent improvement. Mutation in exon 5 of the DOK7 gene was found in both siblings. Patients with congenital myasthenic syndrome with DOK 7 mutation benefit remarkably with salbutamol.

Clinical and neurophysiological response to pharmacological treatment of DOK7 congenital myasthenia in an older patient

The existence of hereditary congenital myasthenic syndromes CMS) has been recognized for decades and mutations in downtream of tyrosine kinase 7 (DOK7), causes approximately 10% of ll CMS [1]. DOK7 CMS induces progressive limb girdle weakness from the rst years of life. Creatine kinase (CK) is normal, but muscle biopsy an appear myopathic [1]. 2-agonists and 3,4-diaminopyridine (3,4-DAP) is used to treat OK7 CMS [2], but results have mainly been reported in chilren and adolescents [3]. In this report we add information about resentation, treatment effect and electrophysiological treatment esponse in an older person with DOK7.

G.P.1: Refinement of diagnosis of Becker muscular dystrophy: Results of re-analysis of DNA samples

The phenotype of Becker muscular dystrophy (BMD) is highly variable, and thus the disorder might be underdiagnosed. In this study we have reviewed the undiagnosed cases among patients referred for suspected BMD in the period 1985–1995. At that time DNA analysis of the DMD gene was the only routinely available diagnostic test for patients suspected of having muscular dystrophy. Over the last decade sequencing techniques have been developed for the detection of small mutations in the DMD gene. Our aim was to investigate whether BMD had been genetically underdiagnosed in the early decade of DNA analysis and, if so, whether we could improve the diagnostic yield by applying new techniques. Previously, in 79 of 185 referrals for BMD testing no deletions or duplications had been found. The original requisition forms for DNA analysis were re-evaluated; Forty-six cases were excluded because clinical data were lacking or not suggestive for BMD or the patients were known to be deceased. In 33 cases the clinical information was compatible with BMD and those were considered potentially relevant for re-analysis of the DMD gene. Sequencing could be performed on 31 stored DNA samples. Six different mutations, including four novel ones, were found. Long term clinical follow-up in these adult males revealed that one patient was asymptomatic, one had mild symptoms and four had lost ambulation due to progressive limb girdle weakness. Conclusion: We conclude that extending DNA analysis by sequencing the DMD gene can be helpful in identifying BMD in male patients in whom previously no deletions or duplications were found. A delayed diagnosis can still be valuable for the proband or the relatives of the BMD patients.

G.P.26: Vitamin D deficiency myopathy in Egypt: A treatable myopathy

Vitamin D deficiency could be due to decreased bioavailability (decreased intake or exposure to sunlight, urinary loss or malabsorption), abnormal metabolism (liver disease, renal disease) or abnormal target tissue response (vitamin D resistant or gastrointestinal disorders). Vitamin D deficiency is one of the causes of osteomalacic myopathy. To highlight the clinical and laboratory characteristics of vitamin D deficiency myopathy in Egypt and to discuss its therapeutic implications. All patients presented with gradual progressive limb-girdle weakness with or without bony pains, pains of limb muscles, low backache or joint pains. All patients had detailed clinical assessment, laboratory study (including serum calcium, phosphorus, alkaline phosphatase, total creatine kinase, parathyroid hormone and 25 (OH) vitamin D levels together with neurophysiological study and muscle biopsy in some cases. 30 patients were found to have vitamin D deficiency myopathy. Most of them were females, adolescents or early adults. Decreased dairy intake and decreased exposure to sunlight were the main causes for their illness. Most of them had stereotyped clinical presentation with marked deficiency of serum calcium, increased serum phosphorus and increased alkaline phosphatase levels. Parathyroid hormone serum level was high and vitamin D serum level was low. Muscle biopsy showed non-specific myopathic changes in studied specimens. Therapy with a combination of daily calcium and vitamin D intake greatly improve both pains and weakness within few months of all patients. Vitamin D deficiency myopathy is a common condition among females in Egypt due to decreased dairy intake and exposure to sunlight. Clinicians must take attention to this type of myopathy as it is a treatable myopathy.

Recomendações para o Diagnóstico da Forma Tardia da Doença de Pompe

Pompe disease is a progressive and debilitating autossomal recessive myopathy due to mutations in lysossomal acid-α-glucosidase. Its late-onset form has a heterogeneous presentation mimicking other neuromuscular diseases, leading to diagnostic challenge. To develop consensus based recommendations for the diagnosis of late-onset Pompe Disease. Bibliographic review and analysis of an opinion questionnaire applied to a group of specialists with expertise in the diagnosis of several myopathies and lysossomal storage disorders. Discussed in consensus meeting. Patients with a progressive limb-girdle weakness, fatigue, cramps and muscle pain should be evaluated with CK levels, electromyography, dynamic spirometry and muscle biopsy in inconclusive cases. Suspected cases and those in which muscle biopsy could not allow other diagnosis should be screened for lysossomal acid-α-glucosidase deficiency with DBS (dried blood spot). The diagnosis should be confirmed by determination of lysossomal acid-α-glucosidase activity in a second sample and lysossomal acid-α-glucosidase gene sequencing.

GFPT1-myasthenia

To identify patients with GFPT1-related limb-girdle myasthenia and analyze phenotypic consequences of the mutations. We performed genetic analysis, histochemical, immunoblot, and ultrastructural studies and in vitro electrophysiologic analysis of neuromuscular transmission. We identified 16 recessive mutations in GFPT1 in 11 patients, of which 12 are novel. Ten patients had slowly progressive limb-girdle weakness responsive to cholinergic agonists with onset between infancy and age 19 years. One patient (no. 6) harbored a nonsense mutation and a second mutation that disrupts the muscle-specific GFPT1 exon. This patient never moved in utero, was apneic and arthrogrypotic at birth, and was bedfast, tube-fed, and barely responded to therapy at age 6 years. Histochemical studies in 9 of 11 patients showed tubular aggregates in 6 and rimmed vacuoles in 3. Microelectrode studies of intercostal muscle endplates in 5 patients indicated reduced synaptic response to acetylcholine in 3 and severely reduced quantal release in patient 6. Endplate acetylcholine receptor content was moderately reduced in only one patient. The synaptic contacts were small and single or grape-like, and quantitative electron microscopy revealed hypoplastic endplate regions. Numerous muscle fibers of patient 6 contained myriad dilated and degenerate vesicular profiles, autophagic vacuoles, and bizarre apoptotic nuclei. Glycoprotein expression in muscle was absent in patient 6 and reduced in 5 others. GFPT1-myasthenia is more heterogeneous than previously reported. Different parameters of neuromuscular transmission are variably affected. When disruption of muscle-specific isoform determines the phenotype, this has devastating clinical, pathologic, and biochemical consequences.

Expanding the Spectrum of ANO5-Muscular Dystrophy: Skeletal Muscle Amyloidosis, Cardiac Arrhythmia and Novel Mutations (PD6.001)

Objective: To investigate the clinical and pathological spectrum of ANO5-muscular dystrophy. Background Anoctamin-5 (ANO5) is a putative calcium-activated chloride channel and is highly expressed in skeletal and cardiac muscles and in bone. Dominant mutations in ANO5 cause gnathodiaphyseal dysplasia, while recessive mutations result in limb-girdle muscular dystrophy or distal myopathy. Design/Methods: Clinical examination, EMG, EKG, echocardiography, muscle histochemical studies, and mutational analysis in 4 unrelated patients. Results:Patient (Pt) 1: A 53-year-old woman with exercise-induced myalgia since childhood, rhabdomyolysis, adult-onset progressive limb-girdle weakness and asymmetric calf atrophy and weakness. Pt2: A 42-year-old man with progressive asymmetric distal and proximal weakness and paroxysmal atrial fibrillation since late 309s. Pt3: A 32-year-old woman with delayed motor milestones, myalgia, progressive limb-girdle weakness since mid 209s, and supraventricular tachyarrhythmia requiring ablation. Pt 4: A 68-year-old man with long standing history of asymptomatic hyper-CKemia followed by weakness of the calf muscles, subsequently extending to the limb-girdle muscles. All patients had elevated CK and myopathic EMG changes. Muscle biopsy revealed nonspecific myopathic changes in Pt1, Pt2, and Pt4; signs of reinnervation in Pt3; and amyloid deposits within the interstitium and blood vessel walls in Pt1 and Pt2. Echocardiogram revealed septal wall global hypokinesis in Pt3 and normal findings in the other patients. All 4 patients harbored two heterozygous ANO5 mutations; Pt2, Pt3 and Pt4 carry novel ANO5 mutations. Conclusions: The presence of cardiac arrhythmia in 2/4 patients suggest that cardiac involvement can occur in ANO5-muscular dystrophy and underlines the need for close cardiac monitoring. The presence of skeletal muscle amyloidosis in 2/4 patients increases the pathological similarity between ANO5-muscular dystrophy and dysferlinopathy and provides a clue to the diagnosis in the absence of dysferlin deficiency and/or dysferlin mutations. Supported by: The Neurology Department at Mayo Clinic, Rochester MN. Disclosure: Dr. Liewluck has nothing to disclose. Dr. Dimberg has nothing to disclose. Dr. Winder has received personal compensation for activities with PreventionGenetics. Dr. Milone has nothing to disclose.

Delayed diagnosis of oculopharyngeal muscular dystrophy in Scotland

IntroductionOculopharyngeal muscular dystrophy (OPMD) presents with progressive ptosis, dysphagia and limb girdle weakness, and is caused by expansion of a trinucleotide tandem repeat within the gene encoding poly-(A) binding protein...

The typical MERRF (A8344G) mutation of the mitochondrial DNA associated with depressive mood disorders

JO N 2 84 1 A8344G [2]. However, major mood disorder has not been reported to date. A 63 year-old female (Patient 1) had three episodes of postpartum psychosis with severe depressive features in her twenties. At age 57 and 60 she had major depression episodes and suicidal ideation. At age 48, progressive proximal limbgirdle muscle weakness started. Examination revealed multiple lipomatosis, hypoacusis, atrophy and weakness in the proximal limb muscles, and ataxia. She had mild memory impairment, depressive mood, and moderate anxiety (Hamilton Score:35). Serum CK was mildly increased. EMG revealed mixed myopathic and neurogenic abnormalities. Brain MRI and EEG were normal. Mild axonal neuropathy was detected in the sural nerve biopsy. In the muscle biopsy 12 % of the fibers were ragged red and COX negative. These fibers contained intramitochondrial paracrystalline inclusions. Patient 2, one of the 43 year-old twin sons of Patient 1 suffered from his late teens from depressive episodes with symptoms of anxiety. From the age of 35 he showed progressive limb girdle weakness. Examination revealed hypoacusis, dysarthria, weakness in the proximal limb muscles, distal type sensory impairment in the legs, and ataxia. He had depressed mood, persisting sense of being depreciated, and loss of critical judgment (Hamilton score:20). Serum and CSF lactate were elevated. ENG revealed axonal sensomotor neuropathy, EMG showed mixed pattern. EEG was normal. Muscle biopsy showed myopathic changes, pleiomorphic mitochondria. Patient 3 (the other twin) at the age of 18 required hospitalization for severe anxiety and phobic manifestations. Presently he is asymptomatic. In his muscle biopsy Maria Judit Molnar Jozsef Perenyi Eva Siska George Nemeth Zoltan Nagy

Atypical facet of Möbius syndrome: Association with facioscapulohumeral muscular dystrophy

We describe a patient with facioscapulohumeral muscular dystrophy (FSHD) associated with Möbius syndrome and congenital ophthalmoplegia. This 7-year-old girl had profound limitation of extraocular movements since birth, congenital facial diplegia, neonatal hypotonia, and progressive limb-girdle weakness. FSHD genetic testing revealed a pathogenic haplotype with a D4Z4 repeat of 30 kb. The father carries the same allele, although is minimally affected. This unusual case expands the genotypic-phenotypic spectrum of FSHD.