Shahnaz Ibrahim

Syndrome of Hepatic Cirrhosis, Dystonia, Polycythemia, and Hypermanganesemia Caused by Mutations in SLC30A10, a Manganese Transporter in Man

Environmental manganese (Mn) toxicity causes an extrapyramidal, parkinsonian-type movement disorder with characteristic magnetic resonance images of Mn accumulation in the basal ganglia. We have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental Mn exposure. Whole-genome mapping of two consanguineous families identified SLC30A10 as the affected gene in this inherited type of hypermanganesemia. This gene was subsequently sequenced in eight families, and homozygous sequence changes were identified in all affected individuals. The function of the wild-type protein and the effect of sequence changes were studied in the manganese-sensitive yeast strain Δpmr1. Expressing human wild-type SLC30A10 in the Δpmr1 yeast strain rescued growth in high Mn conditions, confirming its role in Mn transport. The presence of missense (c.266T>C [p.Leu89Pro]) and nonsense (c.585del [p.Thr196Profs(∗)17]) mutations in SLC30A10 failed to restore Mn resistance. Previously, SLC30A10 had been presumed to be a zinc transporter. However, this work has confirmed that SLC30A10 functions as a Mn transporter in humans that, when defective, causes Mn accumulation in liver and brain. This is an important step toward understanding Mn transport and its role in neurodegenerative processes.

The first inborn error of manganese metabolism caused by mutations in SLC30A10, a newly identified manganese transporter

Abstract Background We have identified an autosomal recessively inherited disorder of manganese metabolism that causes manganese accumulation in liver and brain with characteristic MRI brain appearances of hyperintense basal ganglia on T1-weighted sequences. Most affected individuals present in childhood with difficulties walking and fine motor impairment due to dystonia. Movement disorder is accompanied by liver cirrhosis, and some patients have died at a young age following complications of cirrhosis. An adult-onset form of parkinsonism associated with hepatomegaly and hypermanganesaemia has also been described. Further characteristics of both phenotypes include polycythaemia and features of iron depletion. Methods Homozygosity mapping was performed using an Illumina CytoSNP-12. The candidate gene was sequenced on an ABI sequencer. Functional studies in the manganese-sensitive yeast strain Δpmr1 were performed using Gateway technology (Invitrogen). Findings Homozygosity mapping identified SLC30A10 as the affected gene, and homozygous sequence changes were found in all affected individuals. SLC30A10 had previously been presumed to belong to a class of zinc transporters. However, expression of human wildtype SLC30A10 in Δpmr1 rescued growth in high manganese conditions confirming its role in manganese transport. The presence of missense and nonsense mutations in SLC30A10 failed to restore manganese resistance. Interpretation Evidently, evolutionary changes in the aminoacid sequence have altered the substrate specificity of this transporter from zinc in yeast to manganese in mammalian cells. SLC30A10 is the first recognised human manganese transporter that, when defective, causes two distinct phenotypes—childhood onset dystonia and adult onset parkinsonism—that are associated with hepatic cirrhosis and polycythaemia. Present treatment strategies, including chelation therapy with disodium calcium edetate and iron supplementation, lead to significant improvement of clinical symptoms and blood manganese levels. Funding Action Medical Research.

Description of Guillain-Barre syndrome on the basis of clinical features using Hughes scoring system among children in Karachi, Pakistan

Background: Guillain-Barre syndrome (GBS) is an acquired inflammatory polyneuropathy characterized by rapidly progressive symmetrical flaccid limb weakness and areflexia. Here, we aimed to describe GBS on the basis of clinical features using Hughes scoring system (HSS) in children. Methods: We conducted a descriptive study, retrieving medical records of children between 2–16 years old admitted with GBS during January 2011–December 2013 at Aga Khan University Hospital, Karachi. Information on demographics, predisposing factors of GBS, clinical features at presentation, investigations, managements, short- and long-term outcomes were recorded on data extraction sheet. Ethical approval was obtained before data collection. Results: Totally 31 children with GBS (21 males) were admitted during the study period. The mean age was 6.7 years. Thirteen cases were seen in summer (January–October) followed by 11 in spring (March–May) and 7 in winter (November–February). Preceding illnesses including upper respiratory tract infections in 15 and diarrhea was seen in 4 patients. None of the patients had history of prior immunization. The nerve conduction study/electromyography showed acute inflammatory demyelinating polyradiculoneuropathy in 18 (58%), acute motor axonal neuropathy in 8 (25.8%), acute motor and sensory axonal neuropathy in 3 (9.7%) and Miller Fisher syndrome in 2 (6.5%) patients. Twenty-one patients had received intravenous immunoglobulin, four had plasmapharesis, four had both while two patients received none of these. Ventilator support was required by seven patients. Tracheostomy was performed on two patients. The HSS was calculated at 3-month follow-up. Nineteen children (61.2%) had an HSS score of 0–1, eight had a score of 2–5 (25.8%), and four patients were lost to follow-up. Conclusion: HSS is a good tool to identify and follow children with GBS. More than two-thirds of the patients had recovered complete mobility at 3-month follow-up.