Tumtip Sangruchi

Mutation analysis of the GNE gene in distal myopathy with rimmed vacuoles (DMRV) patients in Thailand

Distal myopathy with rimmed vacuoles (DMRV) is an early‐adult‐onset, distal myopathy caused by a mutation of the UDP‐N‐acetylglucosamine 2 epimerase/N‐acetylmannosamine kinase (GNE) gene. We herein report four Thai patients with DMRV who carried compound heterozygous mutations of the GNE gene including three novel (p.G89R, p.P511T, and p.I656N) and two known mutations (p.A524V and p.V696M). All patients shared p.V696M in one allele. Our study demonstrates the mutation spectrum of the GNE gene in Thai patients with DMRV. Muscle Nerve, 2006

Glutaric aciduria type 2, late onset type in Thai siblings with myopathy.

Reported here is a novel presentation of late onset glutaric aciduria type 2 in two Thai siblings. A 9-year-old boy presented with gradual onset of proximal muscle weakness for 6 weeks. The initial diagnosis was postviral myositis, and then polymyositis. Electromyography and nerve conduction velocity testing indicated a myopathic pattern. Muscle biopsy revealed excessive accumulation of fat. Acylcarnitine profiling led to the diagnosis of glutaric aciduria type 2. Immunoblot analysis of electron-transferring-flavoprotein and its dehydrogenase electron-transferring-flavoprotein dehydrogenase led to mutation analysis of the ETFDH gene, which revealed two different pathogenic mutations in both alleles and confirmed the diagnosis of glutaric aciduria type 2 caused by electron-transferring-flavoprotein dehydrogenase deficiency. The boy recovered completely after treatment. Later, his younger sibling became symptomatic; the same diagnosis was confirmed, and treatment was similarly effective. Acylcarnitine profiling was a crucial investigation in making this diagnosis in the presence of normal urine organic acid findings. Late onset glutaric aciduria type 2, a rare cause of muscle weakness in children, should be included in the differential diagnosis of myopathy.

Novel DYSF mutations in Thai patients with distal myopathy

Dysferlinopathy refers to a variety of autosomal recessive, skeletal muscle disorders due to the mutations of dysferlin-encoding gene, DYSF. It encompasses limb-girdle muscular dystrophy type 2B (LGMD2B), Miyoshi myopathy (MM), distal myopathy with anterior tibial onset (DMAT), isolated hyperCKemia, rigid spine syndrome and congenital muscular dystrophy. Herein, we report five Thai patients with distal myopathy due to dysferlinopathy including four MM and one DMAT patients. Muscle biopsy from one MM patient depicted numerous ring fibers which is an atypical finding in dysferlinopathy. Mutation analysis of DYSF revealed novel compound heterozygous mutations of p.Tyr309X and c.236+1G>T in two related MM patients, known homozygous mutations, p.Arg89X and p.Gln176X, in two MM patients and a heterozygous missense mutation, p.Arg555Trp, in a DMAT patient. Most of the previously reported DMAT patients were Hispanic. To the best of our knowledge, this is the first report of genetically confirmed patients with dysferlinopathy in Thailand.

A novel ECGF1 mutation in a Thai patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive, multisystem disorder, which is clinically defined by ptosis, ophthalmoparesis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and leukoencephalopathy. MNGIE is caused by mutations in the nuclear gene, endothelial cell growth factor 1 (ECGF1), encoding thymidine phosphorylase (TP). ECGF1 mutations cause severe loss of TP activity, abnormal accumulations of thymidine and deoxyuridine in plasma, and alterations of mitochondrial DNA. Here, we report the first Thai patient with MNGIE confirmed genetically by the identification of a homozygous novel ECGF1 gene mutation, c.100insC, which causes a frameshift and premature truncation of TP protein.

A Novel Mutation of the GNE Gene in Distal Myopathy with Rimmed Vacuoles: A Case with Inflammation

Distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive or sporadic early adult-onset myopathy caused by mutations in the UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase (GNE) gene. Characteristic pathologic features of DMRV are rimmed vacuoles on muscle biopsy and tubulofilamentous inclusion in ultrastructural study. Presence of inflammation in DMRV is unusual. We report a sporadic case of DMRV in a 40-year-old Thai man who presented with slowly progressive distal muscle weakness. Gene analysis revealed a compound heterozygous mutation of the GNE gene including a novel mutation c.1057A>G (p.K353E) and a known mutation c.2086G>A (p.V696M). The latter is the most common mutation in Thai DMRV patients. The muscle pathology was compatible with DMRV except for focal inflammation.

Severe plexiform facial neurofibromatosis, type 1 with underdeveloped eyes and a novel NF1 mutation.

A Thai woman, who was affected with neurofibromatosis type 1, was followed up and re‐evaluated at ages 45, 61, and 67 years. Her mother and her three brothers were also affected. The proposita was very severely affected. She was born blind with underdeveloped eyeglobes and had large plexiform neurofibromas on her face. Her eyelids were gigantic and tears drained from the orifice between them. Cutaneous neurofibromas were observed all over her body. A novel mutation c.4821delA was identified in NF1 gene, which predicted truncation of neurofibromin (p.Leu1607fs).

Impact of muscle biopsy on diagnosis and management of children with neuromuscular diseases: A 10-year retrospective critical review

BACKGROUND Muscle biopsy facilitates morphologic, biochemical, and ultrastructural analysis of muscle for the purpose of making definitive neuromuscular diagnosis. However, muscle biopsy is an expensive, invasive, time-consuming, and resource-dependent procedure. The need for general anesthesia in children also increases the risks associated with this procedure. The aim of this study was to investigate the benefits of muscle biopsies performed over a 10-year period, with a focus on indications, suspected and histopathologic diagnosis, and impact on diagnosis and management decisions. METHODS We retrospectively reviewed results of muscle biopsies performed in children at our center during the 2004 to 2014 study period. Clinical presentations, biopsy complications, pathologic results, and changes in management decision were reviewed and analyzed. RESULTS Biopsies from 92 patients were included. Mean age of patients was 7.1years, and 66.3% were male. There were no perioperative complications, and definitive diagnosis was made in 74 patients. Regardless of whether pathologic changes were found or not, information gained from muscle biopsy significantly impacted prognosis and subsequent genetic counseling. CONCLUSIONS Muscle biopsy is a safe and useful diagnostic tool in children suspected of having neuromuscular diseases, especially in those with muscle diseases. Definitive pathologic diagnosis helps to optimize treatment, counseling, and surveillance. THE TYPE OF STUDY AND LEVEL OF EVIDENCE Study of diagnostic test: level 1.

Ophthalmoplegia in congenital neuromuscular disease with uniform type 1 fiber.

Congenital neuromuscular disease with uniform type 1 fiber (CNMDU1) is a rare type of congenital myopathy. It is characterized by early onset of symptoms, mild proximal muscle weakness, hyporeflexia or areflexia, normal serum creatine kinase (CK) levels and myopathic electromyography finding, uniform type 1 fibers, and nonprogression. We report a 2-year-old boy who presented with congenital hypotonia, breathing and feeding difficulty, myopathic facies, proximal muscle weakness, ptosis, total external ophthalmoplegia and delayed motor developmental milestones. Normal serum muscle enzyme and short duration of motor unit potentials on electromyography were noted. Muscle biopsy showed uniformity of type 1 fibers (greater than 99%) and moderate variation in fiber size without specific structural abnormality. Total external ophthalmoplegia may be one of the important clinical manifestations of CNMDU1. It is important to recognize this disorder because it is nonprogressive in nature.

Discordant manifestation in brothers with Miyoshi myopathy

Dysferlinopathy is known to have various clinical manifestations. It is caused by mutations in the DYSF gene and is inherited in an autosomal recessivemanner. The twomain phenotypes areMiyoshimyopathy with predominantly distal weakness and limb-girdle muscular dystrophy type 2B (LGMD2B)with primarily proximalweakness.Miyoshimyopathy typically manifests in young adulthood with atrophy and weakness, especially the gastrocnemius and soleusmuscles. Over several years, the symptoms spread to the thighs and gluteal muscles. Some patients may be asymptomatic or minimally symptomatic with high creatine kinase (CK) level [1]. We report two affected brothers whose ages are one year different, with discordant manifestation in this disease. The elder brother presented with hip and distal leg weakness at the age of 14 years old and was found to have bilateral calf atrophy. CK was 13,678 IU/L. Muscle biopsy showedmarked variation of fiber size, many necrotic and regenerative fibers with or without phagocytosis, and regenerating fibers. Perimysial and perivascular lymphocyte infiltration was observed. The endomysial and perimysial tissues were slightly thickened. Other stainings were unremarkable. Dysferlin staining was negative (Fig. 1A–B). The younger brother was examined at the age of 13 years and was found to be normal. He was asymptomatic with high CK of 12,131 IU/L. After 5-year-follow up, the elder brother at the age of 19 years old had progressive weakness and atrophy of both proximal and distal leg muscles. He could walk only with two-person assistance and mostly used a wheelchair. His CK was persistently elevated in 9000– 29,000 IU/L range despite treatment with coenzyme Q10 and creatine supplement. However, the younger brother remained asymptomatic while his CK was still high in the similar range of 12,000–26,000 IU/L. At the age of 18 years old, he was found to have only minimal calf atrophy without weakness, and hewas still able to participate in sports and school activities. Clinical heterogeneity is common in dysferlinopathy [2]. Some presymptomatic individuals have only a marked elevation of serum CK, but they eventually develop muscle weakness and atrophy. The manifestation of each phenotype, either limb girdle muscular dystrophy (LGMD) or Miyoshi myopathy (MM) can coexist even in the same

Kyphoscoliosis and easy fatigability in a 14-year-old boy

Thepatientwasa14-year-oldThaiboywhopresentedatanorthopedic clinic with kyphoscoliosis first detected 1 yearprior to medical attention. He was the first child of non-consanguineous parents; the pregnancy and delivery wereuneventful.He had normal developmental milestones.Thepatient noticed easy fatigability after exercise which wors-ened during the past year. His younger brother was 10years old and healthy. There was no history ofneuromuscular disease in his family. His father passedaway due to an unrelated incident. General examinationrevealed a body weight of 30 kg and a height of 149 cm,bilateral ptosis, high-arched palate, kyphoscoliosis, andasymmetrical chest wall. Proximal muscle weakness ofgrade 4 by Medical Research Council Scale in all extrem-itiesandareflexiawerenoted.Themuscletonewasnormal.SerumCKwas49 IU/L.Echocardiogramshowedmildpul-monary and tricuspid regurgitation. Pulmonary functiontestsshowedrestrictivelungdisease;theforcedvitalcapac-ity was 1.56 L (51% of predicted). Sleep study revealedapnea-hypopnea index 13.6 per hour associated withsevere oxygen desaturation (minimum SpO