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Journal of Neurology Dec 2020Behr syndrome is a clinically distinct, but genetically heterogeneous disorder characterized by optic atrophy, progressive spastic paraparesis, and motor neuropathy...
BACKGROUND
Behr syndrome is a clinically distinct, but genetically heterogeneous disorder characterized by optic atrophy, progressive spastic paraparesis, and motor neuropathy often associated with ataxia. The molecular diagnosis is based on gene panel testing or whole-exome/genome sequencing.
METHODS
Here, we report the clinical presentation of two siblings with a novel genetic form of Behr syndrome. We performed whole-exome sequencing in the two patients and their mother.
RESULTS
Both patients had a childhood-onset, slowly progressive disease resembling Behr syndrome, starting with visual impairment, followed by progressive spasticity, weakness, and atrophy of the lower legs and ataxia. They also developed scoliosis, leading to respiratory problems. In their late 30's, both siblings developed a hypertrophic cardiomyopathy and died of sudden cardiac death at age 43 and 40, respectively. Whole-exome sequencing identified the novel homozygous c.627_629del; p.(Gly210del) deletion in UCHL1.
CONCLUSIONS
The presentation of our patients raises the possibility that hypertrophic cardiomyopathy may be an additional feature of the clinical syndrome associated with UCHL1 mutations, and highlights the importance of cardiac follow-up and treatment in neurodegenerative disease associated with UCHL1 mutations.
Topics: Ataxia; Cardiomyopathy, Hypertrophic; Child; Hearing Loss; Humans; Intellectual Disability; Mutation; Neurodegenerative Diseases; Optic Atrophy; Pedigree; Spasm; Spastic Paraplegia, Hereditary; Ubiquitin Thiolesterase
PubMed: 32656641
DOI: 10.1007/s00415-020-10059-3 -
BMC Pediatrics Sep 2020Optic atrophy 1 (OPA1) gene mutations are associated with dominantly inherited optic neuropathy resulting in a progressive loss of visual acuity. Compound heterozygous...
BACKGROUND
Optic atrophy 1 (OPA1) gene mutations are associated with dominantly inherited optic neuropathy resulting in a progressive loss of visual acuity. Compound heterozygous or homozygous variants that lead to severe phenotypes, including Behr syndrome, have been reported rarely.
CASE PRESENTATION
Here, we present a 14-month-old boy with early onset optic atrophy, congenital cataracts, neuromuscular disorders, mental retardation, and developmental delay. Combined genetic testing, including whole exome sequencing (WES) and chromosomal microarray analysis, revealed a concurrent OPA1 variant (c.2189 T > C p.Leu730Ser) and de novo chromosome 3q deletion as pathogenic variants leading to the severe phenotype.
CONCLUSIONS
Our case is the first reporting a novel missense OPA1 variant co-occurring with a chromosomal microdeletion leading to a severe phenotype reminiscent of Behr syndrome. This expands the mutation spectrum of OPA1 and inheritance patterns of this disease.
Topics: Ataxia; Chromosomes; GTP Phosphohydrolases; Hearing Loss; Humans; Infant; Intellectual Disability; Male; Mutation; Optic Atrophy; Pedigree; Spasm
PubMed: 32883255
DOI: 10.1186/s12887-020-02309-0 -
Stem Cell Research Sep 2016Human skin fibroblasts were isolated from a 48-year-old patient carrying compound heterozygous mutations (c.610+364G>A and c.1311A>G) in OPA1, responsible for early...
Human skin fibroblasts were isolated from a 48-year-old patient carrying compound heterozygous mutations (c.610+364G>A and c.1311A>G) in OPA1, responsible for early onset optic atrophy complicated by ataxia and pyramidal signs (Behr syndrome; OMIM #210000). Fibroblasts were reprogrammed using episomal plasmids carrying hOCT4, hSOX2, hKLF4, hL-MYC and hLIN28. The generated transgene-free line iPS-OPA1-BEHR showed no additional genomic aberrations, maintained the disease-relevant mutations, expressed important pluripotency markers and was capable to differentiate into cells of all three germ layers in vitro. The generated iPS-OPA1-BEHR line might be a useful platform to study the pathomechanism of early onset complicated optic atrophy syndromes.
Topics: Ataxia; Base Sequence; Cell Differentiation; Cell Line; Cellular Reprogramming; DNA Mutational Analysis; Female; Fibroblasts; GTP Phosphohydrolases; Genotype; Hearing Loss; Heterozygote; Humans; Immunohistochemistry; Induced Pluripotent Stem Cells; Intellectual Disability; Middle Aged; Optic Atrophy; Polymorphism, Single Nucleotide; Spasm; Transcription Factors
PubMed: 27879217
DOI: 10.1016/j.scr.2016.09.012 -
Brain : a Journal of Neurology Jan 2015
Topics: Central Nervous System Diseases; Female; GTP Phosphohydrolases; Humans; Male; Optic Atrophy, Autosomal Dominant
PubMed: 25146916
DOI: 10.1093/brain/awu234 -
Genes Jun 2022Dominant optic atrophy (DOA), MIM # 605290, is the most common hereditary optic neuropathy inherited in an autosomal dominant pattern. Clinically, it presents a... (Review)
Review
Dominant optic atrophy (DOA), MIM # 605290, is the most common hereditary optic neuropathy inherited in an autosomal dominant pattern. Clinically, it presents a progressive decrease in vision, central visual field defects, and retinal ganglion cell loss. A biallelic mode of inheritance causes syndromic DOA or Behr phenotype, MIM # 605290. This case report details a family with Biallelic Optic Atrophy 1 (OPA1). The proband is a child with a severe phenotype and two variants in the OPA1 gene. He presented with congenital nystagmus, progressive vision loss, and optic atrophy, as well as progressive ataxia, and was found to have two likely pathogenic variants in his OPA1 gene: c.2287del (p.Ser763Valfs*15) maternally inherited and c.1311A>G (p.lIle437Met) paternally inherited. The first variant is predicted to be pathogenic and likely to cause DOA. In contrast, the second is considered asymptomatic by itself but has been reported in patients with DOA phenotype and is presumed to act as a phenotypic modifier. On follow-up, he developed profound vision impairment, intractable seizures, and metabolic strokes. A literature review of reported biallelic OPA1-related Behr syndrome was performed. Twenty-one cases have been previously reported. All share an early-onset, severe ocular phenotype and systemic features, which seem to be the hallmark of the disease.
Topics: GTP Phosphohydrolases; Humans; Male; Mutation; Optic Atrophy; Optic Atrophy, Autosomal Dominant; Pedigree
PubMed: 35741767
DOI: 10.3390/genes13061005 -
Epilepsy & Behavior Reports 2024Behr syndrome is associated with compound heterozygous dysfunction in gene and typically presents with a constellation of visual impairment due to early onset optic...
Behr syndrome is associated with compound heterozygous dysfunction in gene and typically presents with a constellation of visual impairment due to early onset optic atrophy, cerebellar ataxia, peripheral neuropathy, deafness, and gastrointestinal motility problems. Our patient with biallelic variants in gene had delayed motor milestones, cerebellar ataxia, and optic atrophy in infancy. At the age of 7 years, he presented with recurrent episodes of super-refractory status epilepticus and metabolic stroke due to underlying mitochondrial dysfunction associated with gene dysfunction. Besides the two rare prior case reports of focal and myoclonic seizures in patients with Behr syndrome, epilepsy in general is not well described in the typical phenotypic spectrum and to the best of our knowledge. Dramatic clinical presentation with recurrent super-refractory status epilepticus and metabolic stroke has not been reported previously. There is only one prior report of metabolic stroke in a patient with Behr syndrome due to gene dysfunction.
PubMed: 38369985
DOI: 10.1016/j.ebr.2024.100652 -
Molecular Medicine Reports Jul 2016Mutations in the optic atrophy 1 gene (OPA1) are associated with autosomal dominant optic atrophy and 20% of patients demonstrate extra-ocular manifestations. In... (Review)
Review
Mutations in the optic atrophy 1 gene (OPA1) are associated with autosomal dominant optic atrophy and 20% of patients demonstrate extra-ocular manifestations. In addition to these autosomal dominant cases, only a few syndromic cases have been reported thus far with compound heterozygous OPA1 mutations, suggestive of either recessive or semi‑dominant patterns of inheritance. The majority of these patients were diagnosed with Behr syndrome, characterized by optic atrophy, ataxia and peripheral neuropathy. The present study describes a 10-year-old boy with Behr syndrome presenting with early‑onset severe optic atrophy, sensorimotor neuropathy, ataxia and congenital cataracts. He had optic atrophy and was declared legally blind at six years old. Electrophysiological, radiological, and histopathological findings were compatible with axonal sensorimotor polyneuropathy. At birth, he presented with a congenital cataract, which has not been previously described in patients with OPA1 mutations. Whole exome sequencing indicated a pair of novel compound heterozygous mutations: p.L620fs*13 (c.1857‑1858delinsT) and p.R905Q (c.G2714A). Neither mutation was observed in controls (n=300), and thus, they were predicted to be pathogenic by multiple in silico analyses. The mutation sites were highly conserved throughout different vertebrate species. The patients parents did not have any ophthalmic or neurologic symptoms and the results of electrophysiological studies were normal, suggestive of an autosomal recessive pattern of inheritance. The present study identified novel compound heterozygous OPA1 mutations in a patient with recessive optic atrophy, sensorimotor neuropathy and congenital cataracts, indicating an expansion of the clinical spectrum of pathologies associated with OPA1 mutations. Thus, OPA1 gene screening is advisable in the workup of patients with recessive optic atrophy, particularly with Behr syndrome and cataracts.
Topics: Ataxia; Biopsy; Cataract; Child; DNA Mutational Analysis; Exome; GTP Phosphohydrolases; Genes, Recessive; Hearing Loss; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Intellectual Disability; Leg; Magnetic Resonance Imaging; Male; Mutation; Optic Atrophy; Optic Atrophy, Autosomal Dominant; Pedigree; Spasm
PubMed: 27150940
DOI: 10.3892/mmr.2016.5209 -
Brain : a Journal of Neurology Oct 2014
Topics: Adolescent; Age of Onset; Ataxia; Blindness; Child; Constipation; DNA; Deglutition Disorders; Female; GTP Phosphohydrolases; Hearing Loss; Heterozygote; Humans; Intellectual Disability; Magnetic Resonance Imaging; Male; Mutation; Optic Atrophy; Optic Atrophy, Autosomal Dominant; Peripheral Nervous System Diseases; Spasm
PubMed: 25012220
DOI: 10.1093/brain/awu184 -
Brain : a Journal of Neurology Jan 2015
Topics: Central Nervous System Diseases; Female; GTP Phosphohydrolases; Humans; Male; Optic Atrophy, Autosomal Dominant
PubMed: 25146915
DOI: 10.1093/brain/awu235 -
Brain : a Journal of Neurology Oct 2014
Topics: GTP Phosphohydrolases; Humans
PubMed: 25012222
DOI: 10.1093/brain/awu187