A. Aeby

Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis

Tyrosine hydroxylase deficiency is an autosomal recessive disorder resulting from cerebral catecholamine deficiency. Tyrosine hydroxylase deficiency has been reported in fewer than 40 patients worldwide. To recapitulate all available evidence on clinical phenotypes and rational diagnostic and therapeutic approaches for this devastating, but treatable, neurometabolic disorder, we studied 36 patients with tyrosine hydroxylase deficiency and reviewed the literature. Based on the presenting neurological features, tyrosine hydroxylase deficiency can be divided in two phenotypes: an infantile onset, progressive, hypokinetic-rigid syndrome with dystonia (type A), and a complex encephalopathy with neonatal onset (type B). Decreased cerebrospinal fluid concentrations of homovanillic acid and 3-methoxy-4-hydroxyphenylethylene glycol, with normal 5-hydroxyindoleacetic acid cerebrospinal fluid concentrations, are the biochemical hallmark of tyrosine hydroxylase deficiency. The homovanillic acid concentrations and homovanillic acid/5-hydroxyindoleacetic acid ratio in cerebrospinal fluid correlate with the severity of the phenotype. Tyrosine hydroxylase deficiency is almost exclusively caused by missense mutations in the TH gene and its promoter region, suggesting that mutations with more deleterious effects on the protein are incompatible with life. Genotype-phenotype correlations do not exist for the common c.698G>A and c.707T>C mutations. Carriership of at least one promotor mutation, however, apparently predicts type A tyrosine hydroxylase deficiency. Most patients with tyrosine hydroxylase deficiency can be successfully treated with l-dopa.

A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome.

Vilain C, Rens C, Aeby A, Balériaux D, Van Bogaert P, Remiche G, Smet J, Van Coster R, Abramowicz M, Pirson I. A novel NDUFV1 gene mutation in complex I deficiency in consanguineous siblings with brainstem lesions and Leigh syndrome.

P43 – 2841: Development coordination disorder (DCD) and attention deficit hyperactivity disorder (ADHD) as the initial presentation of bilateral fronto-parietal polymicrogyria type 2 (BFPP2) secondary to GPR56 mutation

Introduction Bilateral Fronto-Parietal Polymicrogyria type 1 (BFPP1; OMIM 606854) is an autosomic recessive affection usually linked to GPR56. Clinical (mental retardation, cerebellar signs, severe psychomotor delay and symptomatic generalized epilepsy) and radiological (bilateral fronto-parietal polymicrogyria with an anterior to posterior gradient with brainstem and cerebellar hypoplasia) signs are specific. Patients with BFPP without cerebellar or brainstem abnormalities (BFPP2) have a milder phenotype and are not linked to GPR56 mutation (Piao et al., 2005; Bahi-Buisson et al., 2010). We report here a patient with specific learning disorder (Development Coordination Disorder-DCD and attention deficit hyperactivity disorder-ADHD) that presented the radiological characteristics of BFPP2 and harbor a GPR56 mutation. Case report 4-year-old boy with a normal psychomotor and speech development, presenting awkwardness, learning difficulties and ADHD. Familial and personal history was unremarkable. Neurological examination was normal. Neuropsychological tests performed at 5.5 years showed DCD (Mouvement assessment Battery for Children-M-ABC scale –2SD and WPPSI-III: ICV=100, IRP=71, IVT=71 with severe dysgraphia) and ADHD. EEG was normal. He received a multidisciplinary rehabilitation and methylphenidate with an improvement of his learning disabilities even though he needed special school when he left kindergarten. When he was 7, he presented shock-like episodes with absences. Prolonged video-EEG showed 2Hz generalized spikes and waves, atypical absences and tonic seizures. Brain MRI revealed BFPP2. DNA analysis revealed compound heterozygoty in GPR56, parents where heterozygous for GPR56. Conclusion This case is, to our knowledge, the first case of BFPP2 phenotype presenting initially as a specific learning disorder and harbouring compound heterozigoty in GPR56.

T.P.30

We report two brothers, aged 14 and 16, with a mild intellectual deficiency. Both brothers presented recurrent episodes of generalized weakness following effort since the age of 4. At the age of 8, after spending twenty minutes playing in a swimming pool, the youngest brother presented an episode of weakness, together with a painful swelling of the left thigh and myoglobinuria (max CK 540,000xa0UI/l). He was hospitalized in an intensive care unit and treated by intravenous fluids and loop diuretics. 4xa0months later, a muscle biopsy disclosed abnormal vacuolisation with slightly increased muscle lipid content. An extensive workup excluded a mitochondrial disease, a defect of fatty acid oxidation and Mac Ardle disease. At the age of 13, the youngest brother presented a refractory status epilepticus, complicated by rhabdomyolysis and acute renal failure (max CK 710,000xa0UI/l). Physical examination of both brothers, between acute episodes, was completely normal and CK level was approximately 500xa0UI/l ( N PGK1 gene sequencing revealed a splice site consensus sequence change that co-segregates with decreased PGK activity. Its putative functional consequences are currently under investigation. Conclusion: Phosphoglycerate kinase (PGK) deficiency, a rare defect in glycolysis pathway, has its place in the differential diagnosis of metabolic myopathies. The association of exercise intolerance and recurrent episodes of myoglobinuria with haemolytic anaemia, intellectual deficiency or epilepsy is highly suggestive of the disease.