Autozygosity mapping of methylmalonic acidemia associated genes by short tandem repeat markers facilitates the identification of five novel mutations in an Iranian patient cohort.

Isolated Methylmalonic acidemia/aciduria (MMA) is a group of inborn errors of metabolism disease which is caused by defect in methylmalonyl-CoA mutase (MCM) enzyme. The enzyme has a key function in the catabolism of branched chain amino acids (BCAA, isoleucine, and valine), methionine, and threonine. MCM is encoded by a single gene named "MUT". Other subtypes of MMA are caused by mutations in cblA (encoded by MMAA) and cblB (encoded by MMAB), which is involved in the synthesis of methylmalonyl-coenzyme A cofactor. Different types of mutations have been identified as the cause of MMA. However, the mutation spectrum of MMA in Iran has not been studied so far. Here, we aimed to investigate the MMA causative mutations in the Iranian population. Using STR (Short Tandem Repeat) markers, we performed autozygosity mapping to identify the potential pathogenic variants in 11 patients with clinical diagnosis of MMA. Nineteen STR markers which are linked to the MUT, MMAA and MMAB genes (the genes with known causative mutations in MMA) were selected for PCR-amplification using two recently designed multiplex PCR panels. Next, the families that were diagnosed with homozygous haplotypes for the candidate genes were directly sequenced. Five novel mutations (c.805delG, c.693delC, c.223A > T, c.668A > G and c.976A > G in MUT) were identified beside other 4 recurrent mutations (c.361insT in MUT, c.571C > T and c.197-1 G > T in MMAB and c.1075C > T in MMAA). In silico analyses were also performed to predict the pathogenicity of the identified variants. The mutation c.571C > T in MMAB was the most common mutation in our study.

GM2-Gangliosidosis (Sandhoff and Tay Sachs disease): Diagnosis and Neuroimaging Findings (An Iranian Pediatric Case Series).

OBJECTIVE: GM2-Gangliosidosis disease is a rare autosomal recessive genetic disorder that includes two disorders (Tay-Sachs and Sandhoff disease).These disorders cause a progressive deterioration of nerve cells and inherited deficiency in creating hexosaminidases A, B, and AB. MATERIALS & METHODS: Patients who were diagnosed withGM2-Gangliosidosis in the Neurology Department of Mofid Children's Hospital in Tehran, Iran from October 2009 to February 2014were included in our study. The disorder was confirmed by neurometabolic and enzyme level detection of hexosaminidases A, B, and AB in reference to Wagnester Laboratory in Germany. We assessed age, gender, past medical history, developmental status, clinical manifestations, and neuroimaging findings of 9 patients with Sandhoff disease and 9 with Tay Sachs disease. RESULTS: 83% of our patients were the offspring of consanguineous marriages. All of them had a developmental disorder as a chief complaint. 38%of patients had a history of developmental delay or regression and 22% had seizures. The patients with Sandhoff and Tay Sachs disease were followed for approximately 5 years and the follow-up showed all patients were bedridden or had expired due to refractory seizures, pneumonia aspiration, or swallowing disorders. Neuro-imaging findings included bilateral thalamic involvement, brain atrophy, and hypo myelination in near half of our patients (48%). CONCLUSION: According to the results of this study, we suggest that cherry-red spots, hyperacusis, refractory seizures, and relative parents in children with developmental delay and/or regression should be considered for assessment of GM2-Gangliosidosis disease.

Propionic acidemia: diagnosis and neuroimaging findings of this neurometabolic disorder.

OBJECTIVE: Propionic acidemia is one of the rare congenital neurometabolic disorders with autosomal recessive inheritance. This disorder is caused by a defect in the propionyl-CoA carboxylase enzyme and can be presented with life-threatening ketoacidosis, lethargy, failure to thrive, and developmental delay. MATERIALS & METHODS: The patients diagnosed as having propionic acidemia in Neurology Department of Mofid Children's Hospital in Tehran, Iran, between 2002 and 2012 were include in our study. This disorder was confirmed by clinical manifestations, neuroimaging findings, and neurometabolic assessment in the reference laboratory in Germany. Our study was conducted to define the sex, age, gender, past medical history, developmental status, clinical findings, and neuroimaging manifestations in 10 patients with propionic acidemia. RESULTS: Seventy percent of patients were offspring of consanguineous marriages. In this study, only one patient had microcephaly at birth, but at detection time, 30% of patients had head circumference and weight below the 3rd percentile. The patients were followed for approximately 5 years and this follow-up showed that the patients with early diagnosis had a more favorable clinical response. Neuroimaging findings included brain atrophy, white matter and globus pallidus involvement. CONCLUSION: Finally we suggest that early diagnosis and treatment have an important role in the prevention of disease progression.

Methylmalonic acidemia: diagnosis and neuroimaging findings of this neurometabolic disorder (an Iranian pediatric case series).

OBJECTIVE: Methylmalonic acidemia is one of the inborn errors of metabolism resulting in the accumulation of acylcarnitine in blood and increased urinary methylmalonic acid excretion. This disorder can have symptoms, such as neurological and gastrointestinal manifestations, lethargy, and anorexia. MATERIALS & METHODS: The patients who were diagnosed as methylmalonic acidemia in the Neurology Department of Mofid Children's Hospital in Tehran, Iran, between 2002 and 2012 were included in our study. The disorder was confirmed by clinical findings, neuroimaging findings, and neurometabolic and genetic assessment in reference laboratory in Germany. We assessed the age, gender, past medical history, developmental status, clinical manifestations, and neuroimaging findings of 20 patients with methylmalonic acidemia. RESULTS: Eighty percent of the patients were offspring of consanguineous marriages. Half of the patients had Failure to thrive (FTT) due to anorexia; 85% had history of developmental delay or regression, and 20% had refractory seizure, which all of them were controlled. The patients with methylmalonic acidemia were followed for approximately 5 years and the follow-up showed that the patients with early diagnosis had a more favorable clinical response in growth index, refractory seizure, anorexia, and neurodevelopmental delay. Neuroimaging findings included brain atrophy, basal ganglia involvement (often in putamen), and periventricular leukomalacia. CONCLUSION: According to the results of this study, we suggest that early assessment and diagnosis have an important role in the prevention of disease progression and clinical signs.

Biotinidase deficiency: a reversible neurometabolic disorder (an Iranian pediatric case series).

OBJECTIVE: Biotinidase deficiency is one of the rare congenital metabolic disorders with autosomal recessive inheritance. If this disorder is diagnosed in newborn period, could be prevented well from mental and physical developmental delay and most of clinical manifestations. MATERIALS & METHODS: The patients were diagnosed as biotinidase deficiency in Neurology Department of Mofid Children's Hospital in Tehran, Iran, between 2009 and 2012 were included in this study. This study was conducted to define the age, gender, past medical history, developmental status, general appearance, clinical manifestations, neuroimaging findings, and response to treatment in 16 patients with biotinidase deficiency in this department. RESULTS: In clinical presentation, cutaneous lesions were not found in 37% of the patients and 43% patients had not alopecia. 75% patients had abnormal neuroimaging that in 56% of them, generalized brain atrophy and myelination delay were found. Results of the present study showed the efficacy of biotin in early diagnosed patients with seizure and dermatological manifestations. The seizure and skin manifestations were improved after biotin therapy. CONCLUSION: According to the results of this study, we suggest that early assessment and diagnosis have an important role in the prevention of disease progression and clinical signs.

The Association between EEG Abnormality and Behavioral Disorder: Developmental Delay in Phenylketonuria.

Background. Brain defect leading to developmental delay is one of the clinical manifestations of phenylketonuria. The aim of this study was to evaluate the association between EEG abnormality and developmental delay/behavioral disorders in phenylketonuria. Patients and Methods. 105 phenylketonuria patients, who were diagnosed through newborn screening tests or during follow-up evaluation, were enrolled. Patients who were seizure-free for at least six months before the study were included. The developmental score were evaluated by the ASQ questionnaire (age-stage questionnaire) and the test of child symptom inventory-4 (CSI-4), respectively. Results. 55 patients had a history of seizure more than 6 months before the study. Seventy had abnormal EEG (cases) and 35 had normal EEG (controls). There was no significant difference between mean phenylalanine levels in the abnormal and normal EEG groups at the time of diagnosis, after six months and at our evaluation. Distribution of DQ level in the abnormal and normal EEG groups revealed a significant difference. An abnormal EEG was associated with a higher percentage of low DQ levels. Conclusion. Paroxysmal epileptic discharges in PKU patients are important. Treatment of these EEG abnormalities may affect developmental scores or may lead to correction of some behavioral disorders in patients.

Digital and dental malformation and short stature in a patient with neurological problems: a variant of the oculodentodigital dysplasia syndrome or a new syndrome?

Several syndromes have been recognized with digital abnormality and CNS involvement such as oculodentodigital dysplasia (ODDD), Mohr syndrome and Joubert syndrome. We report a patient who was referred to us because of the neurological signs suspicious of metabolic disorders. This case was a 22-year-old woman whose problems began 4 years ago with shortening of memory, ataxia, abnormal gait and diplopia which progressed slowly. She consulted many neurologists and was on treatment with the suspicion of vasculitis, but no response was detected. She had severe short stature, hypoplasia of the middle and distal phalanges of the first, second and third fingers, clinodactyly, abnormal toes, abnormal enamel and missing teeth. She had no characteristic faces of ODDD and ophthalmological abnormality. Our patient might be a variant of ODDD or a new syndrome with somatic and neurologic signs.