Leigh syndrome and hypertrophic cardiomyopathy in an infant with a mitochondrial DNA point mutation (T8993G)

Mutation of mitochondria) (mt) DNA at nucleotide (nt) 8993 has been reported to cause neurogenic weakness, ataxia, retinitis pigmentosa (NARP), or Leigh syndrome (LS). We report a family in whom the mutation was expressed clinically as LS and hypertrophic cardiomyopathy (CMP) in a boy who presented with a history of developmental delay and hypotonia, and who had recurrent lactic acidosis. The mother's first pregnancy resulted in the birth of a stillborn female; an apparently healthy older brother had died suddenly (SIDS) at age 2 months. MtDNA analysis identified the presence of the T8993G point mutation, which was found to be heteroplasmic in the patient's skeletal muscle (90%) and fibroblasts (90%). The identical mutation was present in leukocytes (38%) isolated from the mother, but not from the father or maternal grandmother. Our findings expand the clinical phenotype of the nt 8993 mtDNA mutation to include hypertrophic cardiomyopathy and confirm its cause of LS. © 1994 Wiley-Liss, Inc.     

Leigh syndrome: MRI findings in two children

Leigh syndrome is a progressive neurodegenerative disorder of childhood. The symmetrical necrotic lesions in the basal ganglia and/or brainstem which appear as hyperintense lesions on T2-weighted MRI is characteristic and one of the essential diagnostic criteria. Recognising this MR imaging pattern in a child with neurological problems should prompt the clinician to investigate for Leigh syndrome. We present here two cases of Leigh syndrome due to different biochemical/genetic defects, and discuss the subtle differences in their MR neuroimaging features.     

SURF1-associated Leigh syndrome: a case series and novel mutations

Leigh syndrome (LS) is a mitochondrial disease that typically presents in infancy with subacute neurodegenerative encephalopathy. It is genetically heterogeneous, but mutations in the complex IV assembly genes, particularly SURF1, are an important cause. In this study, SURF1 gene was sequenced in 590 patients with clinical suspicion of LS, complex IV deficiency, or clinical features of mitochondrial disorders. We identified 21 patients with clinical features of LS who are either homozygous or compound heterozygous for SURF1 mutations. Twenty-two different mutations were identified, including 13 novel mutations. Of the 42 mutant alleles, 36 (86%) are null mutations (frameshift, splicing, or nonsense) and 6 (14%) are missense. We have also reviewed the previously reported SURF1 mutations and observed a clustering of mutation in exon 8 of SURF1, suggesting a vital function for this region. Although mutations in SURF1 have been mainly associated with typical LS, five of the patients in this report had an atypical course of LS. There is no definite genotype-phenotype correlation; however, frameshift mutations resulting in protein truncation closer to the C-terminus may carry a better prognosis.     

Biallelic variants in COX4I1 associated with a novel phenotype resembling Leigh syndrome with developmental regression,intellectual disability,and seizures

Autosomal recessive COX4I1 deficiency has been previously reported in a single individual with a homozygous pathogenic variant in COX4I1, who presented with short stature, poor weight gain, dysmorphic features, and features of Fanconi anemia. COX4I1 encodes subunit 4, isoform 1 of cytochrome c oxidase. Cytochrome c oxidase is a respiratory chain enzyme that plays an important role in mitochondrial electron transport and reduces molecular oxygen to water leading to the formation of ATP. Defective production of cytochrome c oxidase leads to a variable phenotypic spectrum ranging from isolated myopathy to Leigh syndrome. Here, we describe two siblings, born to consanguineous parents, who presented with encephalopathy, developmental regression, hypotonia, pathognomonic brain imaging findings resembling Leigh‐syndrome, and a novel homozygous variant on COX4I1, expanding the known clinical phenotype associated with pathogenic variants in COX4I1.     

Case report and novel treatment of an autosomal recessive Leigh syndrome caused by short‐chain enoyl‐CoA hydratase deficiency

Short chain enoyl‐CoA hydratase (SCEH) deficiency leads to a severe form of autosomal recessive Leigh syndrome with inevitable neurological decline and early mortality. SCEH is most notably involved in valine catabolism, a deficiency of which results in various metabolic alterations, including increased levels of the highly reactive metabolite 2‐methacrylyl‐CoA. With no proven treatments available to date, it has been speculated that patients may respond to a valine restricted diet and/or N‐acetylcysteine supplementation, as suggested by early studies of a very similar inborn error of metabolism, 3‐hydroxyisobutyryl‐CoA hydrolase deficiency. We describe a patient with typical Leigh syndrome clinical findings and identified compound heterozygous variants in ECSH1. Valine‐restricted diet was initiated at 6 months of age and N‐acetylcysteine supplementation at 9 months with subsequent improvement in growth and slow progress in developmental milestones. However, at 15 months, the patient aspirated during a breakthrough seizure from which he did not recover and died soon after from related complications. This report highlights some of the challenges that remain in the management and treatment of SCEH deficiency, while demonstrating that a valine restricted diet and N‐acetylcysteine can be safely administered with the potential for clinical improvement.     

Phenotypic variability and mutation hotspot in COX15‐related Leigh syndrome

COX15 mutations were shown to underlie Leigh syndrome (LS), a progressive subacute necrotizing encephalopathy caused by defects in the mitochondrial respiratory chain. Here, two siblings of consanguineous kindred presented in infancy with a syndrome of hypotonia, nystagmus, psychomotor retardation, and pyramidal signs. Toward the end of their second year, both patients developed progressive quadriparesis, convulsions, and pseudobulbar palsy. Similar to two previously reported cases, one of the two affected siblings had severe hypertrophic obstructive cardiomyopathy, hearing loss, and no visual response. Through linkage analysis and whole‐exome sequencing, we identified a homozygous p.R217W mutation in Cytochrome C oxidase assembly protein COX15 homolog. Consistent with the known heterogeneity of mitochondrial diseases in general and that of LS in particular, several phenotypic features were markedly distinguished between the affected siblings and in relation to previous reports of COX15 mutations. Interestingly, of the previously reported five cases of COX15‐mutated patients, all of different ethnic origins, three had a p.R217W mutation. We highlight p.R217W as a hotspot mutation in COX15 and delineate the phenotypic variability, both between the patients we describe and in all cases reported to date.     

A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein‐truncating variant

Leigh syndrome is a mitochondrial disease caused by pathogenic variants in over 85 genes. Whole exome sequencing of a patient with Leigh‐like syndrome identified homozygous protein‐truncating variants in two genes associated with Leigh syndrome; a reported pathogenic variant in PDHX (NP_003468.2:p.(Arg446*)), and an uncharacterized variant in complex I (CI) assembly factor TIMMDC1 (NP_057673.2:p.(Arg225*)). The TIMMDC1 variant was predicted to truncate 61 amino acids at the C‐terminus and functional studies demonstrated a hypomorphic impact of the variant on CI assembly. However, the mutant protein could still rescue CI assembly in TIMMDC1 knockout cells and the patient's clinical phenotype was not clearly distinct from that of other patients with the same PDHX defect. Our data suggest that the hypomorphic effect of the TIMMDC1 protein‐truncating variant does not constitute a dual diagnosis in this individual. We recommend cautious assessment of variants in the C‐terminus of TIMMDC1 and emphasize the need to consider the caveats detailed within the American College of Medical Genetics and Genomics (ACMG) criteria when assessing variants.     

Early‐onset liver disease complicated with acute liver failure in Alstrom syndrome

We report a case of Alstrom syndrome with evidence of extensive hepatic disease diagnosed at five years of age, who subsequently developed acute liver failure and died at eight years of age. Such a case, with the patient dying before the age of ten, has not been described before. The biochemical findings during our patient's liver failure raised the question of a possible mitochondrial function defect in this syndrome. Further investigation of this possibility is needed. © 2001 Wiley‐Liss, Inc.     

Biallelic loss of function variants in SYT2 cause a treatable congenital onset presynaptic myasthenic syndrome

Synaptotagmins are integral synaptic vesicle membrane proteins that function as calcium sensors and regulate neurotransmitter release at the presynaptic nerve terminal. Synaptotagmin‐2 (SYT2), is the major isoform expressed at the neuromuscular junction. Recently, dominant missense variants in SYT2 have been reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment. These variants are thought to have a dominant‐negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated. Here we report seven patients of five families, with biallelic loss of function variants in SYT2, clinically manifesting with a remarkably consistent phenotype of severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings were consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in three patients showed clinical improvement with increased strength and function. This series further establishes SYT2 as a CMS‐disease gene and expands its clinical and genetic spectrum to include recessive loss‐of‐function variants, manifesting as a severe congenital onset presynaptic CMS with potential treatment implications.     

Novel biallelic SZT2 mutations in 3 cases of early‐onset epileptic encephalopathy

The seizure threshold 2 (SZT2) gene encodes a large, highly conserved protein that is associated with epileptogenesis. In mice, Szt2 is abundantly expressed in the central nervous system. Recently, biallelic SZT2 mutations were found in 7 patients (from 5 families) presenting with epileptic encephalopathy with dysmorphic features and/or non‐syndromic intellectual disabilities. In this study, we identified by whole‐exome sequencing compound heterozygous SZT2 mutations in 3 patients with early‐onset epileptic encephalopathies. Six novel SZT2 mutations were found, including 3 truncating, 1 splice site and 2 missense mutations. The splice‐site mutation resulted in skipping of exon 20 and was associated with a premature stop codon. All individuals presented with seizures, severe developmental delay and intellectual disabilities with high variability. Brain MRIs revealed a characteristic thick and short corpus callosum or a persistent cavum septum pellucidum in each of the 2 cases. Interestingly, in the third case, born to consanguineous parents, had unexpected compound heterozygous missense mutations. She showed microcephaly despite the other case and previous ones presenting with macrocephaly, suggesting that SZT2 mutations might affect head size.     

TGDS pathogenic variants cause Catel‐Manzke syndrome without hyperphalangy

Catel‐Manzke syndrome, also known as micrognathia‐digital‐syndrome, is a rare autosomal recessive disorder characterized by the combination of the two cardinal features Pierre‐Robin sequence and bilateral hyperphalangy leading to ulnar clinodactyly (ulnar curvature of the phalanges) and radial deviation (radial angulation at the metacarpophalangeal joint) of the index fingers. Individuals without one of these major hallmarks or with additional hand malformations have been described as atypical or Catel‐Manzke‐like syndrome. Biallelic TGDS pathogenic variants have thus far been detected in eight individuals with typical Catel‐Manzke syndrome and in one fetus with additional features. Here we report on two individuals with TGDS pathogenic variants who presented with mild radial deviation and ulnar clinodactyly of the index fingers but without radiologic signs of hyperphalangy. Furthermore, both individuals have disproportionate short stature, a feature that has not yet been associated with Catel‐Manzke syndrome. Our data broaden the phenotypic spectrum of TGDS‐associated Catel‐Manzke syndrome and expand the indication for diagnostic testing.     

Gene mutation analysis of 175 Chinese patients with early‐onset epileptic encephalopathy

The aim of the study is to investigate the genetic characteristics and clinical features of a cohort of Chinese patients with early‐onset epileptic encephalopathies (EOEEs). Targeted next‐generation sequencing (NGS), focusing on 17 genes, was performed on 175 Chinese patients with EOEEs to screen gene mutations. The mutation rate was 32% (56/175). All mutations were de novo and heterozygous, including 41 novel and 15 reported mutations. Patients with cyclin‐dependent kinase‐like 5 (CDKL5) gene mutation accounted for the largest proportion, 13.1% (23/175). All patients with CDKL5 mutation presented severe psychomotor developmental delay and refractory seizures. The female patients presented obvious Rett‐like features, which were not observed in male patients. Potassium channel, voltage‐gated KQT‐like subfamily Q, member 2(KCNQ2) gene mutations were detected in 13 patients. Patients with this mutation presented with early seizure onset within the first week after birth. Valproate (VPA), levetiracetam (LEV) and topiramate (TPM) were effective in most patients. Patients with specific gene mutations presented some unique clinical features, but not always. Many genes are involved in EOEEs. Targeted NGS showed a high diagnostic yield in patients with EOEEs. These findings provide useful insights for recommending treatment of gene‐associated EOEEs using antiepileptic drugs.     

ECHS1 disease in two unrelated families of Samoan descent: Common variant ‐ rare disorder

Mutations in the short‐chain enoyl‐CoA hydratase (SCEH) gene, ECHS1, cause a rare autosomal recessive disorder of valine catabolism. Patients usually present with developmental delay, regression, dystonia, feeding difficulties, and abnormal MRI with bilateral basal ganglia involvement. We present clinical, biochemical, molecular, and functional data for four affected patients from two unrelated families of Samoan descent with identical novel compound heterozygous mutations. Family 1 has three affected boys while Family 2 has an affected daughter, all with clinical and MRI findings of Leigh syndrome and intermittent episodes of acidosis and ketosis. WES identified a single heterozygous variant in ECHS1 at position c.832G > A (p.Ala278Thr). However, western blot revealed significantly reduced ECHS1 protein for all affected family members. Decreased SCEH activity in fibroblasts and a mild increase in marker metabolites in urine further supported ECHS1 as the underlying gene defect. Additional investigations at the DNA (aCGH, WGS) and RNA (qPCR, RT‐PCR, RNA‐Seq, RNA‐Array) level identified a silent, common variant at position c.489G > A (p.Pro163=) as the second mutation. This substitution, present at high frequency in the Samoan population, is associated with decreased levels of normally spliced mRNA. To our understanding, this is the first report of a novel, hypomorphic allele c.489G > A (p.Pro163=), associated with SCEH deficiency.     

Artery tortuosity syndrome exhibiting early‐onset emphysema with novel compound heterozygous SLC2A10 mutations

We report on a 2‐year‐old Japanese boy with early‐onset pulmonary emphysema, exhibiting dysmorphic face, loose skin, and inguinal and Morgagni hernias. He was admitted to our hospital owing to refractory respiratory infection. On the basis of his clinical features, we investigated the SLC2A10 gene and identified novel compound heterozygous mutations of c.417T > A and c.692G > A, leading to the diagnosis of artery tortuosity syndrome (ATS). This syndrome is an extremely rare autosomal recessive disorder characterized by tortuosity and elongation of the large and medium‐sized arteries, hyperextensible skin, and diverse hernias, mostly reported from Europe and Middle Eastern countries, but not from Asia. Although chronic obstructive pulmonary disease, namely, emphysema, has not been well documented in ATS, it may be likely because TGF‐beta up‐regulation is known to be evoked by SLC2A10 mutations, resulting in reconstruction of pulmonary endothelial cells and emphysema. This is the first report of ATS associated with early‐onset pulmonary emphysema, suggesting that patients with ATS may also require close attention for chronic obstructive pulmonary disease. © 2013 Wiley Periodicals, Inc.     

Mutations in KARS cause early‐onset hearing loss and leukoencephalopathy: Potential pathogenic mechanism

Leukoencephalopathies are a broad class of common neurologic deterioration for which the etiology remains unsolved in many cases. In a Chinese Han family segregated with sensorineural hearing loss and leukoencephalopathy, candidate pathogenic variants were identified by targeted next‐generation sequencing of 144 genes associated with deafness and 108 genes with leukoencephalopathy. Novel compound heterozygous mutations p.R477H and p.P505S were identified in KARS, which encodes lysyl‐tRNA synthetase (LysRS), as the only candidate causative variants. These two mutations were functionally characterized by enzymatic assays, immunofluorescence, circular dichroism analysis, and gel filtration chromatography. Despite no alteration in the dimer‐tetramer oligomerization and cellular distribution by either mutation, the protein structure was notably influenced by the R477H mutation, which subsequently released the protein from the multiple‐synthetase complex (MSC). Mutant LysRSs with the R477H and P505S mutations had decreased tRNA^Lys aminoacylation and displayed a cumulative effect when introduced simultaneously. Our studies showed that mutations in KARS lead to a newly defined subtype of leukoencephalopathy associated with sensorineural hearing impairment. The combined effect of reduced aminoacylation and release of LysRS from the MSC likely underlies the pathogenesis of the KARS mutations identified in this study.     

Analysis copy number variation of Chinese children in early‐onset epileptic encephalopathies with unknown cause

Copy number variations (CNVs) play an important role in the genetic etiology of unknown cause early‐onset epileptic encephalopathies (EOEEs), but the genomic CNVs analysis of Chinese EOEEs children was rare. Here, we identified CNVs by single nucleotide polymorphism array in 116 patients with different subtypes of EOEEs. Of 116 patients 17 (14.66%) carried 19 large CNVs. A total of 14 CNVs in 12 patients were further validated: four of the CNVs were classified as de novo, seven were maternal, and three were paternal. Follow‐up of those 12 patients showed that 5 had been seizure‐free for at least 9 months, 5 had seizures several times per month or per year, and 2 had seizures everyday. But eight patients have profound developmental delay. In this study, we found at least 3.4% of patients had pathogenic CNVs. For the patients, our study laid the foundation for prenatal interventions for their families. Further, we identified potential candidate gene involved in EOEEs. The association of CNVs and clinical features will contribute to the understanding of EOEEs.