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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 -
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 -
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