Iman G. Mahmoud

Biallelic mutations in SNX14 cause a syndromic form of cerebellar atrophy and lysosome-autophagosome dysfunction

Pediatric-onset ataxias often present clinically as developmental delay and intellectual disability, with prominent cerebellar atrophy as a key neuroradiographic finding. Here we describe a new clinically distinguishable recessive syndrome in 12 families with cerebellar atrophy together with ataxia, coarsened facial features and intellectual disability, due to truncating mutations in the sorting nexin gene SNX14, encoding a ubiquitously expressed modular PX domain–containing sorting factor. We found SNX14 localized to lysosomes and associated with phosphatidylinositol (3,5)-bisphosphate, a key component of late endosomes/lysosomes. Patient-derived cells showed engorged lysosomes and a slower autophagosome clearance rate upon autophagy induction by starvation. Zebrafish morphants for snx14 showed dramatic loss of cerebellar parenchyma, accumulation of autophagosomes and activation of apoptosis. Our results characterize a unique ataxia syndrome due to biallelic SNX14 mutations leading to lysosome-autophagosome dysfunction.

Rapid progression and mortality of lysosomal acid lipase deficiency presenting in infants.

Purpose:The purpose of this study was to enhance understanding of lysosomal acid lipase deficiency (LALD) in infancy.Methods:Investigators reviewed medical records of infants with LALD and summarized data for the overall population and for patients with and without early growth failure (GF). Kaplan–Meier survival analyses were conducted for the overall population and for treated and untreated patients.Results:Records for 35 patients, 26 with early GF, were analyzed. Prominent symptom manifestations included vomiting, diarrhea, and steatorrhea. Median age at death was 3.7 months; estimated probability of survival past age 12 months was 0.114 (95% confidence interval (CI): 0.009-0.220). Among patients with early GF, median age at death was 3.5 months; estimated probability of survival past age 12 months was 0.038 (95% CI: 0.000-0.112). Treated patients (hematopoietic stem cell transplant (HSCT), n = 9; HSCT and liver transplant, n = 1) in the overall population and the early GF subset survived longer than untreated patients, but survival was still poor (median age at death, 8.6 months).Conclusions:These data confirm and expand earlier insights on the progression and course of LALD presenting in infancy. Despite variations in the nature, onset, and severity of clinical manifestations, and treatment attempts, clinical outcome was poor.Genet Med 18 5, 452–458.

Selective screening for inborn errors of metabolism by tandem mass spectrometry in Egyptian children: A 5 year report

OBJECTIVE In order to enhance awareness and promote registry for inborn errors of metabolism (IEMs) in Egypt, we aimed to evaluate the prevalence and main clinical findings of IEMs detectable by tandem mass spectrometry (MS/MS) among high risk pediatric patients presenting to our tertiary care facility at Cairo University Childrens Hospital over a period of 5 years and to compare the disease burden in Egypt in the absence of a national screening program for inherited metabolic disorders with other populations. METHODS During this period 3380 Egyptian children were suspected of having IEMs based on clinical/laboratory presentation and were analyzed by MS/MS. Confirmatory testing was performed according to flagged analyte by MS/MS using a different sample type such as plasma or urine or by a different technique such as GC/MS. RESULTS A relatively high number of patients (203/3380 (6%)) were confirmed with 17 different types of IEMs. Averages for age at diagnosis for different disorders ranged from 2.5 months to 6.6 years with general developmental delay and irreversible neurological damage being the most common presenting features (75.9% and 65.5%, respectively). Amino acid disorders (127/203 (62.6%)), mainly phenylketonuria (100/203 (49.3%)), were the most encountered, followed by organic acidemias (69/203 (34%)), while fatty acid oxidation defects (7/203 (3.4%)) were relatively rare. 88% of patients were born to consanguineous parents. CONCLUSIONS The development of a nationwide screening program for IEMs is mandatory for early detection of these potentially treatable disorders, prompt and properly timed therapeutic intervention and prevention of the devastating neurological outcomes.

Inborn errors of metabolism detectable by tandem mass spectrometry in Egypt: The first newborn screening pilot study.

Objectives To estimate the burden of metabolic disorders detectable by tandem mass spectrometry in Egypt, through a pilot expanded newborn screening programme at Cairo University Childrens Hospital in 2008, and examining the results of 3,900 clinically at-risk children, investigated at Cairo University Children’s Hospital for the same disorders over the past 7 years using the same technology. Methods Dried blood spots of 25,276 healthy newborns from three governorates in Upper, Middle, and Lower Egypt were screened, to give a representative sample of the Egyptian newborn population. Based on the pilot study outcomes and the results of clinically suspected children, we estimated the total birth prevalence of tandem mass spectrometry detectable metabolic disorders, and the relative frequency of several individual disorders. Results Among the healthy newborns, 13 metabolic disorder cases (five phenylketonuria [1:5,000], two methylmalonic acidemia, and isovaleric acidemia [1:12,500], one each of maple syrup urine disease, propionic acidemia, β-ketothiolase deficiency, and primary carnitine deficiency [1:25,000]) were confirmed, giving a total birth prevalence of 1:1944 live births. Among the clinically suspected children, 235 cases were diagnosed, representing a much wider disease spectrum. Conclusions Egypt has one of the highest reported birth prevalence rates for metabolic disorders detectable by tandem mass spectrometry. Early diagnosis and management are crucial for the survival and well-being of affected children. A nationwide NBS programme by tandem mass spectrometry is recommended.

Biallelic variants in KIF14 cause intellectual disability with microcephaly

Kinesin proteins are critical for various cellular functions such as intracellular transport and cell division, and many members of the family have been linked to monogenic disorders and cancer. We report eight individuals with intellectual disability and microcephaly from four unrelated families with parental consanguinity. In the affected individuals of each family, homozygosity for likely pathogenic variants in KIF14 were detected; two loss-of-function (p.Asn83Ilefs*3 and p.Ser1478fs), and two missense substitutions (p.Ser841Phe and p.Gly459Arg). KIF14 is a mitotic motor protein that is required for spindle localization of the mitotic citron rho-interacting kinase, CIT, also mutated in microcephaly. Our results demonstrate the involvement of KIF14 in development and reveal a wide phenotypic variability ranging from fetal lethality to moderate developmental delay and microcephaly.

Mutations in FA2H in three Arab families with a clinical spectrum of neurodegeneration and hereditary spastic paraparesis

To the Editor FA2H encodes fatty acid 2-hydroxylase, involved in the alpha-hydroxylation of the N-acyl ceramide moiety of sphingolipid fatty acids, essential components of myelin (1). Mutations in FA2H were identified in patients with recessive childhood onset spasticity, dystonia, cognitive dysfunction and periventricular white matter disease (2) and later extended to include neurodegeneration with brain iron accumulation (NBIA) (3), as well as in a recessive complicated form of hereditary spastic paraplegia (SPG35, MIM#612319) (4, 5). We report seven patients from three unrelated consanguineous Arab families each with a novel homozygous FA2H gene mutation presenting with progressive spastic paraparesis and features of NBIA, highlighting the

P97 – 3032: Epidemiological study of neurometabolic diseases diagnosed at Cairo University Children Hospital: A two years outcome

Objective To study the prevalence of inherited metabolic disorders diagnosed at the Unit of inherited metabolic disease at Cairo University Children Hospital (CUCH), focusing on the wide variability of clinical presentations of these diseases as well as on the risk factors and demographic distribution. Methods 1289 patients were evaluated clinically at the neurometabolic unit from 2008 to 2010 with retrospective analysis of the data. Results Out of 1289 patients, 120 Patients were diagnosed as Phenylketonuria: 67 males (55.8%) and 53 females (44.2%), with age of presentation range (few days to 14 years). The remaining 1169 patients: 672 males (57.5%) with age range (1 week–18 years). Positive consanguinity was observed in 60.3% of patients. Excluding the PKU group: neurological manifestations were predominantly reported as 34.2% of clinical findings, non neurologic manifestations as 16.9%, dysmorphic/skeletal abnormalities and isolated short stature: 12.5%. Positive risk factors: 11.1%. Dermatological manifestations: 5.1%, ocular/auditory defects: 4.8%, failure to thrive: 4.7%. Metabolic disturbances: 4.3%. Organomegaly: 3.4%. CNS anomalies and neuroimaging findings: 2.7% and an asymptomatic group: 0.2%. A final diagnosis was confirmed in 782/1289 patients (60.6%) among which 288 (36.8%) were metabolic disorders: Aminoacidopathies were diagnosed in 146 patients (18.7%), lysosomal storage disorders in 78 (10%), organic acidurias in 18 (2.3%), dyslipideamias in 10 (1.3%), other leukodystrophies in 10 (1.3%), mitochondrial disorders in 9 (1.2%), carbohydrate metabolic disorders in 8 (1%), peroxisomal disorders in 6 (0.8%), metal disorders in 3 (0.4%), urea cycle disorders in 3 (0.4%) and 1 (0.1%) had a congenital disorder of glycosylation. 494 patients (63.2%) had genetic and other non metabolic diseases. Conclusion Inherited inborn errors of metabolism and genetic non metabolic disorders are not uncommon in Egyptian population due to high rate of consanguinous marriages. Therefore, we recommend initiation of a national newborn screening program or at least, a selective screening for the high risk families for early diagnosis and future prevention of disabilities caused by these disorders.

P80 – 2638: Molybdenum cofactor and isolated sulphite oxidase deficiencies in Egyptian children: Report of 6 cases

Objective To describe the clinical, biochemical and molecular genetic findings in Egyptian children with Molybdenum Cofactor and isolated sulfite oxidase deficiencies, for the first time in Egypt. Methods Six Egyptian patients from different pedigrees with confirmed Molybdenum co Factor or isolated sulfite oxidase deficiencies were included in the study. All the patients were subjected to a thorough general and neurologic examination, expanded metabolic screen and urine organic acid profile, brain MRI and quantitation of S-sulphocysteine and xanthine in urine by LC-Ms/Ms and 5/6 patients had molecular analysis for MCOS1 gene. Results All six patients presented with intractable seizures immediately after birth. Microcephaly, severe neurodevelopmental delay, swallowing dysfuction, axial hypotonia, spastic quadriparesis, hyperekeplexia, characteristic craniofacial abnormalities as narrow bifrontal diameter and deeply seated eyes was present in all 6 patients. Extraneurologic manifestations in the form of hypertrophic cardiomyopathy, and xanthine stones was detected in one patient each, both suffering from MCO deficiency. two patients were diagnosed biochemicaly as isolated sulphite oxidase deficiency and four patients with molybdenum cofactor deficiency. MRI of all patients was characterized by multiple severe volume loss & subcortical cysts. The common mutation detected was MCOS1. Conclusion Molybdenum co factor and sulphite oxidase deficiencies are a diagnosable inborn errors of metabolism. Brain MRI is crucial in pointing to the diagnosis by the presence of multiple cortical cysts simulating hypoxic cystic encephalomalacia.