Nicolaides-Baraitser syndrome (NCBRS) is a rare disease caused by a mutation in the
gene. Clinical features include craniofacial dysmorphia and abnormalities of the limbs, as well as intellectual ...disorder and often epilepsy. Hepatotoxicity is a rare complication of the therapy with valproic acid (VPA) and a mutation of the polymerase γ (
) might lead to a higher sensitivity for liver hepatotoxicity. We present a patient with the coincidence of two rare diseases, the NCBRS and additionally a
mutation in combination with a liver hepatotoxicity. The co-occurrence in children for two different genetic diseases is discussed with the help of literature review.
Neuromuscular junctions (NMJs) are synapses that transmit impulses from motor neurons to skeletal muscle fibers leading to muscle contraction. Study of hereditary disorders of neuromuscular ...transmission, termed congenital myasthenic syndromes (CMS), has helped elucidate fundamental processes influencing development and function of the nerve-muscle synapse. Using genetic linkage, we find 18 different biallelic mutations in the gene encoding glutamine-fructose-6-phosphate transaminase 1 (GFPT1) in 13 unrelated families with an autosomal recessive CMS. Consistent with these data, downregulation of the GFPT1 ortholog gfpt1 in zebrafish embryos altered muscle fiber morphology and impaired neuromuscular junction development. GFPT1 is the key enzyme of the hexosamine pathway yielding the amino sugar UDP-N-acetylglucosamine, an essential substrate for protein glycosylation. Our findings provide further impetus to study the glycobiology of NMJ and synapses in general.
The heterooctameric mitochondrial trifunctional protein (MTP), composed of four α- and β-subunits harbours three enzymes that each perform a different function in mitochondrial fatty acid ...β-oxidation. Pathogenic variants in the MTP genes (HADHA and HADHB) cause MTP deficiency, a rare autosomal recessive metabolic disorder characterized by phenotypic heterogeneity ranging from severe, early-onset, cardiac disease to milder, later-onset, myopathy and neuropathy. Since metabolic myopathies and neuropathies are a group of rare genetic disorders and their associated muscle symptoms may be subtle, the diagnosis is often delayed. Here we evaluated data of 161 patients with myopathy and 242 patients with neuropathy via next generation sequencing (NGS) and report the diagnostic yield in three patients of this cohort by the detection of disease-causing variants in the HADHA or HADHB gene. The mitigated phenotypes of this treatable disease were missed by the newborn screening, highlighting the importance of phenotype-based NGS analysis in patients with rare and clinically very variable disorders such as MTP deficiency.
•MTP deficiency is a rare metabolic disorder characterized by phenotypic heterogeneity.•The diagnosis of MTP deficiency is often delayed.•Pathogenic variants in HADHA and HADHB cause MTP deficiency.•Phenotype-based NGS-analysis should be used to identify the cause of MTP deficiency disorders.
Altered autophagy accompanied by abnormal autophagic (rimmed) vacuoles detectable by light and electron microscopy is a common denominator of many familial and sporadic non‐inflammatory muscle ...diseases. Even in the era of next generation sequencing (NGS), late‐onset vacuolar myopathies remain a diagnostic challenge. We identified 32 adult vacuolar myopathy patients from 30 unrelated families, studied their clinical, histopathological and ultrastructural characteristics and performed genetic testing in index patients and relatives using Sanger sequencing and NGS including whole exome sequencing (WES). We established a molecular genetic diagnosis in 17 patients. Pathogenic mutations were found in genes typically linked to vacuolar myopathy (GNE, LDB3/ZASP, MYOT, DES and GAA), but also in genes not regularly associated with severely altered autophagy (FKRP, DYSF, CAV3, COL6A2, GYG1 and TRIM32) and in the digenic facioscapulohumeral muscular dystrophy 2. Characteristic histopathological features including distinct patterns of myofibrillar disarray and evidence of exocytosis proved to be helpful to distinguish causes of vacuolar myopathies. Biopsy validated the pathogenicity of the novel mutations p.(Phe55*) and p.(Arg216*) in GYG1 and of the p.(Leu156Pro) TRIM32 mutation combined with compound heterozygous deletion of exon 2 of TRIM32 and expanded the phenotype of Ala93Thr‐caveolinopathy and of limb‐girdle muscular dystrophy 2i caused by FKRP mutation. In 15 patients no causal variants were detected by Sanger sequencing and NGS panel analysis. In 12 of these cases, WES was performed, but did not yield any definite mutation or likely candidate gene. In one of these patients with a family history of muscle weakness, the vacuolar myopathy was eventually linked to chloroquine therapy. Our study illustrates the wide phenotypic and genotypic heterogeneity of vacuolar myopathies and validates the role of histopathology in assessing the pathogenicity of novel mutations detected by NGS. In a sizable portion of vacuolar myopathy cases, it remains to be shown whether the cause is hereditary or degenerative.
•The reported case of congenital myopathy illustrates the phenotypic spectrum of PLEC-related diseases (“plectinopathies”).•A thorough reassessment of the patient´s neuromuscular phenotype revealed ...mild but characteristic skin blistering (epidermolysis bullosa simplex, EBS).•The case illustrates the importance of deep phenotyping of neuromuscular patients and highlights the chances by “reverse phenotyping” following genetic testing clues.
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.
•Pathogenic variants in ATP1A3 are known to be associated with three distinct neurological syndromes including AHC, RDP and CAPOS.•This study suggests the broader diversity of ATP1A3-related ...disorders.•Atypical features were observed in two patients expanding the phenotypic spectrum of ATP1A3-related disorders.•Three novel causative variants were identified expanding the genotypic spectrum of ATP1A3.
Mutations in the ATP1A3 gene are known to be the cause of three distinct neurological syndromes including alternating hemiplegia of childhood (AHC), rapid-onset dystonia parkinsonism (RDP) and cerebellar ataxia, arefexia, pes cavus, optic atrophy and sensorineural hearing impairment (CAPOS). Recent studies have suggested the broader diversity of ATP1A3-related disorders. This study aimed to investigate the clinical spectrum in patients carrying causative mutations within the ATP1A3 gene.
The medical histories of nine unrelated patients with diverse phenotypes harboring variants in ATP1A3 were retrospectively analyzed after they were referred to a tertiary epilepsy center in one of the two different health care systems (Germany or Thailand). Clinical features, neurophysiological data, imaging results, genetic characteristics and treatments were reviewed.
Three patients harbor novel mutations in the ATP1A3 gene. Atypical clinical features and imaging findings were observed in two cases, one with hemiplegia-hemiconvulsion-epilepsy syndrome, and the other with neurodegeneration with brain iron accumulation. All nine patients presented with intellectual impairment. Alternating hemiplegia of childhood (AHC) was the most common phenotype (67%). Flunarizine and topiramate led to symptom reduction in 83% and 25% of AHC cases administered, respectively.
The present case series expands the clinical and genetic spectrum of ATP1A3-related disorders.
Deficiency of adenosine deaminase 2 (ADA2) due to homozygous or compound heterozygous mutations in the cat eye syndrome chromosome region, candidate 1 (
) gene causes an autoimmune phenotype with ...systemic vasculitis affecting the skin, inner organs, and the central nervous system. Typically, stroke has been reported to follow systemic inflammatory disease and predominantly affects posterior and central brain areas. Here, we describe one of the rare patients in whom acute mesencephalic stroke preceded systemic inflammation and presented as initial clinical symptom. Symptoms typical for ADA2 deficiency such as fever, livedo racemosa, abdominal colics, arthralgias, and Raynaud phenomenon were observed later. Moreover, angiography of cerebral arteries did not reveal typical vasculitic findings supporting the hypothesis that alternative mechanism of vascular occlusion might have caused the stroke. ADA2 deficiency should be considered in patients with childhood stroke despite the absence of systemic inflammation and cerebral vasculitis.
While mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is typically associated with mutations in the nuclear gene encoding for thymidine phosphorylase (
ECGF1, TYMP
), a similar clinical ...phenotype was described in patients carrying mutations in the nuclear-encoded polymerase gamma (
POLG1
) as well as a few mitochondrial tRNA genes. Here we report a novel mutation in the mitochondrial tRNA
Val
(
MTTV
) gene in a girl presenting with clinical symptoms of MNGIE-like gastrointestinal dysmotility and cachexia. Clinical, histological, biochemical and single cell investigations were performed. The heteroplasmic m.1630A>G mutation was detected in the mitochondrial tRNA
Val
(
MTTV
) gene in the patient’s muscle, blood leukocytes and myoblasts, as well as in blood DNA of the unaffected mother. We provide clinical, biochemical, histological, and molecular genetic evidence on the single cell level for the pathogenicity of this mutation. Our finding adds to the genetic heterogeneity of MNGIE-like gastrointestinal symptoms and highlights the importance of a thorough genetic workup in case of suspected mitochondrial disease.
Congenital myasthenic syndromes are caused by different genetic defects affecting proteins expressed at the neuromuscular junction. Recently, the first molecular genetic defect resulting in a ...presynaptic congenital myasthenic syndrome has been reported: Recessive loss-of-function mutations in
CHAT, the gene encoding choline acetyltransferase, were described in five congenital myasthenic syndrome families. In this study, we investigated three patients from two independent Turkish kinships. Clinically, all patients presented with moderate myasthenic symptoms including ptosis and muscle weakness with increased fatigability. Multiple episodes of sudden apnea were reported for all patients. One child suffering from a second, unrelated disorder, i.e. hepatocellular carcinoma, showed a severe myasthenic phenotype, requiring permanent ventilation. Genetically, we identified a novel missense mutation (I336T) in the
CHAT gene homozygously in all three patients. Haplotype analysis revealed that the mutant allele cosegregates with the clinical phenotype in both families (maximum combined two-point LOD-score of 2.46 for
D10S1793). In summary, we confirm that
CHAT mutations are responsible for a clinically distinct form of congenital myasthenic syndrome, characterized by episodic apnea. Infections and stress may lead to a life-threatening failure of neuromuscular transmission in congenital myasthenic syndrome with episodic apnea. The observation of the same mutation (I336T) in two independent Turkish kinships may suggest a common origin, i.e. founder.
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