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1.
Pediatr Neurol ; 96: 40-47, 2019 07.
Article in English | MEDLINE | ID: mdl-30926181

ABSTRACT

BACKGROUND: Tetrahydrobiopterin is an essential cofactor for the hydroxylation of aromatic amino acids phenylalanine, tyrosine, and tryptophan. Therefore, tetrahydrobiopterin deficiency results in hyperphenylalaninemia as well as dopamine and serotonin depletion in the central nervous system. The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the second step of de novo synthesis of tetrahydrobiopterin, and its deficiency is the most frequent cause of tetrahydrobiopterin metabolism disorders. METHOD: We conducted a retrospective chart review of 28 subjects from 24 families with molecularly confirmed 6-pyruvoyltetrahydropterin synthase deficiency from six centers in three Arab countries. We reviewed clinical, biochemical, and molecular data. We also reviewed previously published cohorts of subjects with 6-pyruvoyltetrahydropterin synthase deficiency. RESULTS: Similar to previous observations, we show that early treatment (less than two months) is associated with better outcome. We identify eight PTS variants in 24 independent families. The most common variant is (c.238A>G; p.M80V) with an allele count of 33%. We also identify one novel variant (c.2T>G; p.?). CONCLUSION: The deficiency of 6-pyruvoyltetrahydropterin synthase is relatively common in the Arab population and should be considered in individuals with hyperphenylalaninemia. More natural history studies with comprehensive biochemical and molecular genetics data are needed for a robust base for the development of future therapy.


Subject(s)
Arabs , Consanguinity , Phenylketonurias , Phosphorus-Oxygen Lyases/deficiency , Adolescent , Arabs/genetics , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Infant, Premature , Infant, Small for Gestational Age , Male , Phenylketonurias/drug therapy , Phenylketonurias/genetics , Phenylketonurias/metabolism , Phenylketonurias/physiopathology , Phosphorus-Oxygen Lyases/genetics , Phosphorus-Oxygen Lyases/metabolism , Retrospective Studies
2.
Clin Genet ; 95(2): 310-319, 2019 02.
Article in English | MEDLINE | ID: mdl-30561787

ABSTRACT

Defects in the peroxisomes biogenesis and/or function result in peroxisomal disorders. In this study, we describe the largest Arab cohort to date (72 families) of clinically, biochemically and molecularly characterized patients with peroxisomal disorders. At the molecular level, we identified 43 disease-causing variants, half of which are novel. The founder nature of many of the variants allowed us to calculate the minimum disease burden for these disorders in our population ~1:30 000, which is much higher than previous estimates in other populations. Clinically, we found an interesting trend toward genotype/phenotype correlation in terms of long-term survival. Nearly half (40/75) of our peroxisomal disorders patients had documented survival beyond 1 year of age. Most unusual among the long-term survivors was a multiplex family in which the affected members presented as adults with non-specific intellectual disability and epilepsy. Other unusual presentations included the very recently described peroxisomal fatty acyl-CoA reductase 1 disorder as well as CRD, spastic paraparesis, white matter (CRSPW) syndrome. We conclude that peroxisomal disorders are highly heterogeneous in their clinical presentation. Our data also confirm the demonstration that milder forms of Zellweger spectrum disorders cannot be ruled out by the "gold standard" very long chain fatty acids assay, which highlights the value of a genomics-first approach in these cases.


Subject(s)
Arabs , Peroxisomal Disorders/epidemiology , Peroxisomal Disorders/etiology , Arabs/genetics , Biomarkers , Brain/abnormalities , Brain/diagnostic imaging , Cohort Studies , Consanguinity , Cost of Illness , Disease Management , Disease Susceptibility , Facies , Female , Genetic Association Studies , Genetic Predisposition to Disease , Humans , Magnetic Resonance Imaging , Male , Mutation , Pedigree , Peroxisomal Disorders/diagnosis , Peroxisomal Disorders/therapy , Phenotype , Population Surveillance , Prognosis
3.
J Child Neurol ; 32(6): 543-549, 2017 05.
Article in English | MEDLINE | ID: mdl-28135894

ABSTRACT

Serine biosynthesis defects can present in a broad phenotypic spectrum ranging from Neu-Laxova syndrome, a lethal disease with multiple congenital anomalies at the severe end, to an infantile disease with severe psychomotor retardation and seizures as an intermediate phenotype, to a childhood disease with intellectual disability at the mild end. In this report we present 6 individuals from 3 families with infantile phosphoglycerate dehydrogenase (PGDH) deficiency who presented with psychomotor delay, growth failure, microcephaly, and spasticity. The phenotype was variable with absence of seizures in 2 sisters in family 1 and 1 infant in family 2 and seizures with pronounced happy affect in 3 sisters in family 3. The initiation of serine treatment had pronounced effect on seizures and spasticity in the sisters in family 3, but minimal developmental effects on the children in families 1 and 2. With such phenotypic variability, the diagnosis of PGDH deficiency can be challenging.


Subject(s)
Abnormalities, Multiple , Brain Diseases , Carbohydrate Metabolism, Inborn Errors/complications , Fetal Growth Retardation , Ichthyosis , Limb Deformities, Congenital , Microcephaly/complications , Mutation/genetics , Phosphoglycerate Dehydrogenase/deficiency , Phosphoglycerate Dehydrogenase/genetics , Psychomotor Disorders/complications , Seizures/complications , Abnormalities, Multiple/diagnostic imaging , Abnormalities, Multiple/etiology , Abnormalities, Multiple/genetics , Abnormalities, Multiple/therapy , Adolescent , Brain Diseases/diagnostic imaging , Brain Diseases/etiology , Brain Diseases/genetics , Brain Diseases/therapy , Carbohydrate Metabolism, Inborn Errors/diagnostic imaging , Carbohydrate Metabolism, Inborn Errors/genetics , Child, Preschool , Family Health , Female , Fetal Growth Retardation/diagnostic imaging , Fetal Growth Retardation/etiology , Fetal Growth Retardation/genetics , Fetal Growth Retardation/therapy , Humans , Ichthyosis/diagnostic imaging , Ichthyosis/etiology , Ichthyosis/genetics , Ichthyosis/therapy , Infant , Limb Deformities, Congenital/diagnostic imaging , Limb Deformities, Congenital/etiology , Limb Deformities, Congenital/genetics , Limb Deformities, Congenital/therapy , Male , Microcephaly/diagnostic imaging , Microcephaly/etiology , Microcephaly/genetics , Microcephaly/therapy , Phenotype , Psychomotor Disorders/diagnostic imaging , Psychomotor Disorders/genetics , Seizures/diagnostic imaging , Seizures/genetics , Serine/biosynthesis , Young Adult
4.
BMC Neurol ; 15: 205, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26471939

ABSTRACT

BACKGROUND: Pompe disease is a rare autosomal recessive disorder caused by a deficiency of the lysosomal enzyme alpha-glucosidase responsible for degrading glycogen. Late-onset Pompe disease has a complex multisystem phenotype characterized by a range of symptoms. METHODS: An expert panel from the Middle East and North Africa (MENA) region met to create consensus-based guidelines for the diagnosis and treatment of late-onset Pompe disease for the MENA region, where the relative prevalence of Pompe disease is thought to be high but there is a lack of awareness and diagnostic facilities. RESULTS: These guidelines set out practical recommendations and include algorithms for the diagnosis and treatment of late-onset Pompe disease. They detail the ideal diagnostic workup, indicate the patients in whom enzyme replacement therapy should be initiated, and provide guidance on appropriate patient monitoring. CONCLUSIONS: These guidelines will serve to increase awareness of the condition, optimize patient diagnosis and treatment, reduce disease burden, and improve patient outcomes.


Subject(s)
Consensus , Glycogen Storage Disease Type II/diagnosis , Glycogen Storage Disease Type II/therapy , Practice Guidelines as Topic , Africa, Northern/epidemiology , Glycogen Storage Disease Type II/epidemiology , Glycogen Storage Disease Type II/genetics , Humans , Middle East/epidemiology
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