Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome (ORPHA:496641)
A rare, severe early-onset neurodegenerative encephalopathy characterized mainly by developmental delay (DD) / developmental regression (DR), epilepsy, cortical atrophy, secondary hypomyelination and thin corpus callosum. Additional features include secondary microcephaly, hypotonia, spasticity, optic atrophy and skeletal anomalies.
Epidemiology
The prevalence is unknown. To date, approximately 39 cases have been reported in the literature.
Clinical description
Presentation is typically in the first year of life with severe developmental delay or regression and epilepsy, with progressive cerebral atrophy. Other neurologic problems include spasticity, hypotonia, optic atrophy, ataxia, thin corpus callosum, and secondary hypomyelination. Most of the patients also have secondary microcephaly, and postnatal growth retardation. Additional features include behavioral problems (aggressiveness, hyperactivity, and agitation), and skeletal anomalies (scoliosis, hip dislocation and plagiocephaly). There are no typical facial dysmorphisms. More recently, three additional patients with less severe phenotypes (including autism spectrum disorder and occasional generalized tonic-clonic seizures responding well to antiepileptic drugs) were described.
Etiology
This syndrome is caused by biallelic pathogenic variants in TBCD gene (17q25.3), encoding tubulin folding co-factor D (TBCD), one of five co-chaperones required for microtubule assembly dynamics. Pathogenic TBCD variants affect TBCD stability and function, resulting in disturbed microtubule dynamics. Recent studies suggest specific genotype-phenotype correlations, relating phenotypic expression to the level of dysfunction of the residual protein caused by the pathogenic variants.
Diagnostic methods
Molecular genetic testing approaches may include single-gene molecular genetic testing (Sanger sequencing) based on clinical findings and neuroimaging findings, as well as Next Generation Sequencing (NGS)-based multigene panel or a more comprehensive genomic testing (whole-exome sequencing or whole-genome sequencing).
Differential diagnosis
Differential diagnoses include most epileptic encephalopathies, such as Undetermined early-onset epileptic encephalopathy and Lennox-Gastaut syndrome and mitochondrial encephalopathies.
Antenatal diagnosis
Prenatal diagnosis can be offered if the disease-causing mutations have been identified.
Genetic counseling
The pattern of inheritance is autosomal recessive, meaning that an affected patient has two mutated alleles of TBCD gene. Genetic counseling should be offered to the parents of affected individuals. Each parent of an affected child is usually an asymptomatic carrier of one pathogenic TBCD variant. At each conception, the parents of an affected individual have a 25% risk of having an affected child, a 50% chance of having a child who is an asymptomatic carrier, and a 25% risk of having a child who is neither affected nor a carrier.
Management and treatment
Management should be multidisciplinary, usually addressing DD/DR and control of seizures. It can include physical, occupational and speech therapy. Epilepsy should be treated with antiepileptic drugs (such as sodium valproate and clonazepam) and ketogenic diet which, as well as pyridoxine, show limited success in controlling seizures.
Prognosis
Prognosis depends on the severity of the disease and the presence of seizures. In general, prognosis is poor, with severe to profound global psychomotor developmental delay and refractory epilepsy. Some patients evolve with respiratory failure and early death.

                            Last update: 
                            March 2021


                            - Expert reviewer(s): 
                            Dr Marcia RODRIGUES | ITHACA* - Dr Marta P. SOARES | ITHACA*


                                * European Reference Network