Behr Syndrome Research Articles

OPA1 trans‐splicing: A gene therapy approach to treat OPA1‐related optic neuropathies

AbstractDominant Optic Atrophy is a blinding disease related in 70% of cases to OPA1 variants. OPA1 variants are leading to haplo‐insufficiency or dominant negative effects, leading in 20% of cases to a syndromic presentation, with neurosensorial hearing loss as the most prevalent secondary symptom. Bi‐allelic OPA1 variants are also leading to the Behr syndrome, a severe polyneuropathy involving CNS and PNS symptoms.With the objective to generate a versatile ocular gene therapy for OPA1 patients, we designed a trans‐splicing strategy as a molecular process allowing to correct all OPA1 mRNA transcripts with variants located in and downstream of the GTPase domain, while respecting the normal expression pattern of the 8 OPA1 isoforms, related to alternative splicing occurring before exon 6. Notably, this strategy can theoretically correct most of the haplo‐insufficient and dominant‐negative variants, and should not result in OPA1 over‐expression, whatever the level of the therapeutic vector expression, as the trans‐splicing process uses the endogenous OPA1 pre‐mRNAs to generate a mature‐RNA (mRNA) devoid of the pathogenic variant.We shall present our latest results concerning the feasibility of this approach, and its possible transfer to a clinical trial.

Autosomal Recessive Optic Atrophies

Autosomal recessive optic atrophies are extremely rare and mostly seen with multisystemic diseases. Optic atrophy may occur at birth or in the neonatal period. Severe visual impairment, nystagmus, and pronounced optic disc pallor may be observed. In visual field examination, varying degrees of peripheral visual field defects and paracentral scotoma can be seen. Autosomal recessive optic atrophy can be seen in several disorders including Behr syndrome, Type III 3-methylglutaconic aciduria (OpticAtrophy Plus Syndrome or Costeff Optic Atrophy Syndrome), Wolfram syndrome (DIDMOAD), autosomal recessive optic atrophy with progressive hearing loss and polyneuropathy, Spastic-Quadriplegia-Dementia-Death (Opticochleodentate Degeneration), and Spinocerebellar ataxia. These disorders should also be considered in the differential diagnosis in cases with optic atrophy in early childhood. It is possible to diagnose these cases with a good clinical evaluation, genetic investigations, and pedigree analysis. Early diagnosis can reduce morbidity and mortality due to these disorders. It is also possible to increase the quality of life of the patients with periodic examinations and early rehabilitation.

Concurrent OPA1 mutation and chromosome 3q deletion leading to Behr syndrome: a case report

BackgroundOptic 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 presentationHere, 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.ConclusionsOur 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.

Behr syndrome and hypertrophic cardiomyopathy in a family with a novel UCHL1 deletion

BackgroundBehr 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.MethodsHere, 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.ResultsBoth 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.ConclusionsThe 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.

Generation of optic atrophy 1 patient-derived induced pluripotent stem cells (iPS-OPA1-BEHR) for disease modeling of complex optic atrophy syndromes (Behr syndrome)

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.

ID 55 – Sensory neuropathy in children presenting with Behr syndrome due to OPA1 mutations

Behr syndrome is a complex genetic disorder occurring in children. It associates optic nerve atrophy and spinocerebellar degeneration (ataxia, pyramidal signs), some patients also presenting with peripheral neuropathy. Transmission is generally autosomal recessive and in some cases is related to mutation in OPA1 , a gene encoding a dynamin-related GTPase. 4 children (age 3–14 y-o) with severe visual loss and balance impairment due to OPA1 gene mutations underwent electrodiagnostic (EDX) examination. They presented with early visual loss, mixed cerebellar and proprioceptive ataxia. Some also had pyramidal signs. Compound heterozygous OPA1 mutations were found in all cases. EDX examination demonstrated a severe sensory neuropathy with absent sensory potentials or dramatic decrease of the amplitude, in contrast with normal motor nerve conduction parameters and needle EMG. To date, compound heterozygosity for OPA1 has been proven in only three patients from two unrelated families and neuropathy was not specifically assessed. This is therefore the first report demonstrating the occurrence of severe sensory neuropathy in such cases. Peripheral neuropathy sometimes represents a useful help in the diagnosis of a neurological or metabolic disease occurring in children. The search for sensory neuropathy in children with optic atrophy can be helpful in orientating the genetic diagnosis.

Early‐onset Behr syndrome due to compound heterozygous mutations in OPA1

SummaryBehr syndrome is an early‐onset and severe syndromic optic atrophy which is probably heterogeneous. Recently, a heterozygous mutation in OPA1 was reported in an adult‐onset Behr‐like syndrome. Heterozygous mutations in OPA1 are the main causes of autosomal dominant optic atrophy (DOA). As many as 20% of patients with DOA exhibit extra‐ocular signs including deafness, external ophthalmoplegia, ataxia, peripheral neuropathy and, myopathy. Aside from these autosomal dominant forms, only few syndromic cases have so far been linked to compound heterozygous OPA1 mutations suggestive of either recessive or semi‐dominant inheritance. However, the clinical spectrum of these emerging double‐mutant OPA1‐related disorders remains to be characterized. We report on four children affected with Behr syndrome associated with compound heterozygous OPA1 mutations. These children were similarly affected with an early‐onset neurological syndrome associating a severe optic atrophy (4/4), cerebellar ataxia (4/4), peripheral neuropathy (4/4), digestive involvement (2/4) and deafness (1/4). This report confirms the importance of searching an OPA1 compound heterozygosity in paediatric cases of syndromic optic neuropathy.

Behr syndrome with homozygous C19ORF12 mutation

ObjectiveBehr syndrome, first described in 1909 by the ophthalmologist Carl Behr, is a clinical entity characterised by a progressive optic atrophy, ataxia, pyramidal signs and mental retardation. Some reported cases have been found to carry mutations in the OPA1, OPA3 or C12ORF65 genes which are known causes of pure optic atrophy or optic atrophy complicated by movement disorder. MethodsWe present the long-term observation of two Turkish sisters with Behr syndrome. We performed neurophysiological, imaging and molecular genetic studies to identify the underlying genetic cause in our patients. ResultsMagnetic resonance imaging of the brain showed bilateral hypointense signals in the basal ganglia which prompted us to consider neurodegeneration with brain iron accumulation (NBIA) as a differential diagnosis. Molecular genetic studies revealed a homozygous mutation in the C19ORF12 gene which has been previously reported in patients with a subtype of NBIA, mitochondrial membrane protein-associated neurodegeneration (MPAN). ConclusionWe expand the spectrum of genetic causes of Behr syndrome. Genetic testing of patients presenting with Behr syndrome should include C19ORF12 mutation screening.

Sensory neuropathy in children presenting with Behr syndrome due to OPA1 mutations (P2.035)

Sensory neuropathy in children presenting with Behr syndrome due to OPA1 mutations (P2.035)

Reply: Early-onset Behr syndrome due to compound heterozygous mutations in OPA1

Reply: Early-onset Behr syndrome due to compound heterozygous mutations in OPA1

P29 Behr's syndrome is a mitochondrial disease due to autosomal recessive mutations in the C12orf65 gene

P29 Behr's syndrome is a mitochondrial disease due to autosomal recessive mutations in the C12orf65 gene

Behr's Syndrome is Typically Associated with Disturbed Mitochondrial Translation and Mutations in the C12orf65 Gene.

BackgroundBehr’s syndrome is a classical phenotypic description of childhood-onset optic atrophy combined with various neurological symptoms, including ophthalmoparesis, nystagmus, spastic paraparesis, ataxia, peripheral neuropathy and learning difficulties.ObjectiveHere we describe 4 patients with the classical Behr’s syndrome phenotype from 3 unrelated families who carry homozygous nonsense mutations in the C12orf65 gene encoding a protein involved in mitochondrial translation.MethodsWhole exome sequencing was performed in genomic DNA and oxygen consumption was measured in patient cell lines.ResultsWe detected 2 different homozygous C12orf65 nonsense mutations in 4 patients with a homogeneous clinical presentation matching the historical description of Behr’s syndrome. The first symptom in all patients was childhood-onset optic atrophy, followed by spastic paraparesis, distal weakness, motor neuropathy and ophthalmoparesis.ConclusionsWe think that C12orf65 mutations are more frequent than previously suggested and screening of this gene should be considered not only in patients with mitochondrial respiratory chain deficiencies, but also in inherited peripheral neuropathies, spastic paraplegias and ataxias, especially with pre-existing optic atrophy.

Spastic paraplegia in 'dominant optic atrophy plus' phenotype due to OPA1 mutation

Sir, We read the papers by Yu-Wai-Man et al. (2010) and Marelli et al. (2011) with much interest. The authors described three families with dominant optic atrophy plus phenotype due to OPA1 mutations presenting spastic paraplegia among the extra-ocular neurological features. Two families, reported by Yu-Wai-Man et al . (2010), harboured a deletion c.876-878del(TGT) and a nonsense GTPase mutation c.899C>T, respectively, both resulting in premature termination codons. The affected members presented neuropathy in addition to spastic paraplegia and dominant optic atrophy. Marelli et al. (2011) described a third family in which a missense mutation c.1652G>A in the dynamin domain was associated with Behr syndrome. We report here, a patient in whom a deletion c.2708_2711delTTAG of OPA1 was associated with dominant optic atrophy, spastic paraplegia, Duane retraction syndrome, migraine with atypical aura, patent foramen ovale and muscle fibre abnormalities. Considering the previous reports, we extend the mutations of OPA1 as possibly responsible for dominant optic atrophy plus phenotypes presenting spastic paraplegia, and identify some features shared by patients with optic atrophy plus and spastic pyramidal involvement. The proband, a 28-year-old Italian female belonging to a family from Sicily, has suffered from loss of central vision due to optic atrophy since childhood. She was referred to our unit for the onset, appeared a few years earlier, of slowly progressive …

Heterozygous OPA1 mutations in Behr syndrome

ARTICLE Sir, We read with interest the paper by Yu-Wai-Man et al. (2010) on patients with dominant optic atrophy-plus with OPA1 mutations, which follows on previous reports by the same group (Amati-Bonneau et al. , 2008; Hudson et al. , 2008), reporting the relatively high frequency (∼20%) and the large spectrum of extra-ocular neurological involvement in OPA1 disease. Here, we extend the clinical spectrum of OPA1 mutations to Behr syndrome, characterized by early-onset optic atrophy associated with pyramidal signs, ataxia and sometimes, posterior column sensory loss and mental retardation (Behr 1909; Thomas et al. , 1984). This clinical entity is probably a heterogeneous group of disorders, whose real causes are mostly unknown. In most cases, autosomal recessive inheritance has been suspected. A few patients with typical Behr syndrome and several with Costeff syndrome, a Behr syndrome-like disease associating optic atrophy with extrapyramidal signs, were shown to have type III 3-methylglutaconic aciduria (MGA type III), a recessive disease characterized …

Reply: Heterozygous OPA1 mutations in Behr syndrome

Sir, We were very interested to read the fascinating clinical descriptions of two brothers who presented with childhood-onset optic atrophy and subsequently developed progressive spastic paraparesis and mild ataxia (Marelli et al ., 2010). We agree that the heterozygous c.1652G>A (p.C551Y) missense mutation in exon 17 of OPA1 is likely to be the cause of their neurological disorder, consistent with a dominant optic atrophy ‘plus’ (DOA+) phenotype. This mutation was not identified in the brothers’ mother; and the father, who is deceased, was not thought to be visually or neurologically affected. De novo OPA1 mutations are rare, accounting for <4% of all reported cases (Cohn et al ., 2007). It is therefore much more likely that the father was either non-penetrant, a phenomenon observed in up to 20% of OPA1 carriers, or visually asymptomatic, …

Familial Behr syndrome-like phenotype with autosomal dominant inheritance

Behr syndrome is an autosomal recessive disease characterized by early-onset ataxia, optic atrophy and other signs such as pyramidal tract dysfunction. Autosomal dominant inheritance has also been described. In this case report we present a family pedigree of patients with an inherited autosomal dominant Behr syndrome-like phenotype emphasizing their clinical and neuroimaging features.

Atrophie optique, cataracte et signes extra-pyramidaux par mutation du gène OPA3

In 1961, Garcin et al. described a family with several members affected with optic atrophy associated with cataract, and neurological symptoms. The authors believed this condition to be distinct from other diseases known at that time, e.g. the Behr syndrome, Marinesco-Sjogren syndrome and Friedreich's ataxia. This family was followed over a period of 40 years and genes known to be responsible for optic atrophy were sequenced. The G277A mutation of OPA3 gene was responsible for this familial disease. A new clinical entity is identified: autosomal dominant optic atrophy and cataract, due to a heterozygous mutation of the OPA3 gene, a nuclear gene encoding a mitochondrial protein.

Behr syndrome variant with tremor treated by VIM stimulation

Behr syndrome was first described in 1909 as a syndrome of heredofamilial optic atrophy, visual disturbances, nystagmus, and variable pyramidal tract signs. The syndrome has been reported in both sexes. So far, tremor has not been reported to be part of Behr Syndrome. We present the case of a 51-year-old man with a rare complicated dominant inherited cerebellar ataxia with accompanying visual loss and tremor (CICALVT) resembling a Behr Syndrome variant who suffered from advanced visual deterioration since childhood and progressive spastic paraparesis for 15 years. Furthermore, the patient presented increasing tremor of both hands for 5 years. The successful treatment of the tremor using deep brain stimulation (DBS) of the ventral intermediate thalamic nucleus (VIM) is reported. Our case indicates that deep brain stimulation of the ventral intermediate nucleus is an adequate operative intervention that can help to reduce tremor even in patients with complicated movement disorders.

Musculoskeletal deformities in Behr syndrome.

Seventeen children with Behr syndrome were investigated, focusing on the musculoskeletal deformities and long-term outcome. Behr syndrome is characterized by optic atrophy beginning in early childhood associated with ataxia, spasticity, mental retardation, and posterior column sensory loss. The ataxia, spasticity, and muscle contractures, mainly of the hip adductors, hamstrings, and soleus, are progressive and become more prominent in the second decade. In 70% of the patients, contractures developed in the lower limbs, requiring surgery mainly for the Achilles tendon, hamstrings, and adductor longus. At last follow-up at an average age of 21.7 years (range, 8-31 years), 13 of the patients are housebound walkers, 2 are nonfunctional walkers, and 2 are nonwalkers.

Síndrome de Behr. Presentación de siete casos

To present the clinical and radiological findings of a large series of cases of Behr's syndrome. We studied 7 cases, 6 of whom were 3 pairs of siblings, with clinical alterations compatible with Behr's syndrome which were studied from clinical, genetic and biochemical points of view. In 5 cases magnetic resonance (MR) imaging was used. All patients had marked pyramidal signs, pallor, optic atrophy and normal laboratory findings in the biochemical investigations done to rule out metabolic disorders. MR showed atrophy of the cerebellum which was marked in 3 cases and moderate in 2. In the other two cases it was not used, since it was not available when those cases were studied. Behr's syndrome is not usually considered when studying a patient with ataxia associated with other pyramidal and ocular alterations, due to the theoretically diverse origins of the condition which is a syndrome, not a disease. Perhaps the presence of frank atrophy of the cerebellum may differentiate it from many other clinically similar disorders, which do not however show true cerebellar ataxia.