Clinical Spectrum of Hereditary Spastic Paraplegia in Children : A study of 74 cases

Objectives: The aim of the study was to explore the spectrum of hereditary spastic paraplegia (HSP) in children in Oman. Methods: This retrospective study was carried out between January 1994 and August 2011 on children with delayed development, gait disorders and motor handicaps, with signs of symmetrical pyramidal tract involvement. A detailed perinatal and family history, including the age of onset of symptoms, was recorded. The children were labelled as having either the pure or complicated form of HSP based on the established diagnostic criteria. In families with more than one affected child, parents and all other siblings were also examined. Results: Within the study, 74 children from 31 families were diagnosed with HSP. Parental consanguinity was seen in 91% of cases, with 44 children (59.4%) experiencing onset of the disease under one year of age. Complicated HSP was the most common type, seen in 81.1%. Speech involvement, mental retardation, and epilepsy were the most common associated abnormalities. Nonspecific white matter changes and corpus callosum abnormalities were noted in 24.3% of cases on magnetic resonance imaging. Conclusion: The study described clinical features of 74 children with HSP. Autosomal recessive complicated HSP was seen in 81.1% of cases.

Guidelines for acute management of hyperammonemia in the Middle East region

BACKGROUND: Hyperammonemia is a life-threatening event that can occur at any age. If treated, the early symptoms in all age groups could be reversible. If untreated, hyperammonemia could be toxic and cause irreversible brain damage to the developing brain. OBJECTIVE: There are major challenges that worsen the outcome of hyperammonemic individuals in the Middle East. These include: lack of awareness among emergency department physicians about proper management of hyperammonemia, strained communication between physicians at primary, secondary, and tertiary hospitals, and shortage of the medications used in the acute management of hyperammonemia. Therefore, the urge to develop regional guidelines is extremely obvious. METHOD: We searched PubMed and Embase databases to include published materials from 2011 to 2014 that were not covered by the European guidelines, which was published in 2012. We followed the process of a Delphi conference and involved one preliminary meeting and two follow-up meetings with email exchanges between the Middle East Hyperammonemia and Urea Cycle Disorders Scientific Group regarding each draft of the manuscript. RESULTS AND DISCUSSION: We have developed consensus guidelines based on the highest available level of evidence. The aim of these guidelines is to homogenize and harmonize the treatment protocols used for patients with acute hyperammonemia, and to provide a resource to not only metabolic physicians, but also physicians who may come in contact with individuals with acute hyperammonemia. CONCLUSION: These suggested guidelines aim to ease the challenges faced by physicians dealing with acute hyperammonemia in the region. In addition, guidelines have demonstrated useful collaboration between experts in the region, and provides information that will hopefully improve the outcomes of patients with acute hyperammonemia

Guidelines for acute management of hyperammonemia in the Middle East region

BACKGROUND: Hyperammonemia is a life-threatening event that can occur at any age. If treated, the early symptoms in all age groups could be reversible. If untreated, hyperammonemia could be toxic and cause irreversible brain damage to the developing brain. OBJECTIVE: There are major challenges that worsen the outcome of hyperammonemic individuals in the Middle East. These include: lack of awareness among emergency department physicians about proper management of hyperammonemia, strained communication between physicians at primary, secondary, and tertiary hospitals, and shortage of the medications used in the acute management of hyperammonemia. Therefore, the urge to develop regional guidelines is extremely obvious. METHOD: We searched PubMed and Embase databases to include published materials from 2011 to 2014 that were not covered by the European guidelines, which was published in 2012. We followed the process of a Delphi conference and involved one preliminary meeting and two follow-up meetings with email exchanges between the Middle East Hyperammonemia and Urea Cycle Disorders Scientific Group regarding each draft of the manuscript. RESULTS AND DISCUSSION: We have developed consensus guidelines based on the highest available level of evidence. The aim of these guidelines is to homogenize and harmonize the treatment protocols used for patients with acute hyperammonemia, and to provide a resource to not only metabolic physicians, but also physicians who may come in contact with individuals with acute hyperammonemia. CONCLUSION: These suggested guidelines aim to ease the challenges faced by physicians dealing with acute hyperammonemia in the region. In addition, guidelines have demonstrated useful collaboration between experts in the region, and provides information that will hopefully improve the outcomes of patients with acute hyperammonemia

A mutation of EPT1 (SELENOI) underlies a new disorder of Kennedy pathway phospholipid biosynthesis.

Mutations in genes involved in lipid metabolism have increasingly been associated with various subtypes of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative motor neuron disorders characterized by spastic paraparesis. Here, we report an unusual autosomal recessive neurodegenerative condition, best classified as a complicated form of hereditary spastic paraplegia, associated with mutation in the ethanolaminephosphotransferase 1 (EPT1) gene (now known as SELENOI), responsible for the final step in Kennedy pathway forming phosphatidylethanolamine from CDP-ethanolamine. Phosphatidylethanolamine is a glycerophospholipid that, together with phosphatidylcholine, constitutes more than half of the total phospholipids in eukaryotic cell membranes. We determined that the mutation defined dramatically reduces the enzymatic activity of EPT1, thereby hindering the final step in phosphatidylethanolamine synthesis. Additionally, due to central nervous system inaccessibility we undertook quantification of phosphatidylethanolamine levels and species in patient and control blood samples as an indication of liver phosphatidylethanolamine biosynthesis. Although this revealed alteration to levels of specific phosphatidylethanolamine fatty acyl species in patients, overall phosphatidylethanolamine levels were broadly unaffected indicating that in blood EPT1 inactivity may be compensated for, in part, via alternate biochemical pathways. These studies define the first human disorder arising due to defective CDP-ethanolamine biosynthesis and provide new insight into the role of Kennedy pathway components in human neurological function

Role of FANCM in Alternative Lengthening of Telomeres (ALT) Human Cells

Most immortal human cells maintain their telomeres by up-regulating the enzyme telomerase. Approximately 10-15% of immortal cells maintain their telomere lengths by a recombination-based mechanism termed alternative lengthening of telomeres (ALT). Human ALT cells are characterized by ALT associated promyelocytic bodies (APBs) that contain proteins involved in DNA damage response and repair. Our lab has found significant colocalization of several components of the Fanconi Anemia (FA) pathway with telomeres and demonstrated that knockdown of FANCD2 leads to ALT-specific increase in the amount of telomeric DNA as well as increased aneuploidy and cell death. In this study, we examined the role of FANCM in telomere maintenance in ALT cells. We found a significant colocalization of FANCM with telomeres in two ALT cell lines. Knockdown of FANCM was associated with reduced growth, increases in the size of TRF2 foci and in the amount of telomeric DNA. These data suggest that FANCM plays a role in telomere length regulation and maintenance.MAS

Syndrome of Inappropriate Antidiuretic Hormone Secretion in a Patient with Uncontrolled Tyrosinaemia Type 1

Syndrome of inappropriate antidiuretic hormone (SIADH) secretion is a recognisable complication of acute porphyria. We report a nine-year-old female patient with hereditary tyrosinaemia type 1 and poor adherence to nitisinone therapy who presented with acute abdominal pain, vomiting and lethargy at Sultan Qaboos University Hospital, Muscat, Oman in 2016. She subsequently developed generalised tonic-clonic seizures attributable to severe hyponatremia that met the diagnostic criteria of SIADH. The acute porphyria screen also appeared positive. The patient responded well to fluid restriction and was discharged home without immediate neurological sequelae. Although acute porphyria is also a recognised complication of uncontrolled tyrosinaemia type 1, to the best of the authors’ knowledge, no patient with tyrosinaemia type 1 has been reported to present with SIADH. Keywords: Tyrosinemia Type 1; Hyponatremia; Inappropriate ADH Syndrome; Case Report; Oman

Transient response to high‐dose niacin therapy in a patient with NAXE deficiency

Abstract Background NAXE‐encephalopathy or early‐onset progressive encephalopathy with brain edema and/or leukoencephalopathy‐1 (PEBEL‐1) and NAXD‐encephalopathy (PEBEL‐2) have been described recently as mitochondrial disorders causing psychomotor regression, hypotonia, ataxia, quadriparesis, ophthalmoparesis, respiratory insufficiency, encephalopathy, and seizures with the onset being usually within the first three years of life. It usually leads to rapid disease progression and death in early childhood. Anecdotal reports suggest that niacin, through its role in nicotinamide adenine dinucleotinde (NAD) de novo synthesis, corrects biochemical derangement, and slows down disease progression. Reports so far have supported this observation. Methods We describe a patient with a confirmed PEBEL‐1 diagnosis and report his clinical response to niacin therapy. Moreover, we systematically searched the literature for PEBEL‐1 and PEBEL‐2 patients treated with niacin and details about response to treatment and clinical data were reviewed. Furthermore, we are describing off‐label use of a COX2 inhibitor to treat niacin‐related urticaria in NAXE‐encephalopathy. Results So far, seven patients with PEBEL‐1 and PEBEL‐2 treated with niacin were reported, and all patients showed a good response for therapy or stabilization of symptoms. We report a patient exhibiting PEBEL‐1 with an unfavorable outcome despite showing initial stabilization and receiving the highest dose of niacin reported to date. Niacin therapy failed to halt disease progression or attain stabilization of the disease in this patient. Conclusion Despite previous positive results for niacin supplementation in patients with PEBEL‐1 and PEBEL‐2, this is the first report of a patient with PEBEL‐1 who deteriorated to fatal outcome despite being started on the highest dose of niacin therapy reported to date

Severe Acute Disseminated Encephalomyelitis Mimicking Leukodystrophy in a Child

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A founder mutation in CA5A causing intrafamilial and interfamilial phenotypic variability in a cohort of 18 patients with carbonic anhydrase VA deficiency

Abstract Carbonic anhydrase VA (CA‐VA) deficiency is a rare cause of hyperammonemia caused by biallelic mutations in CA5A. Most patients present with hyperammonemic encephalopathy in early infancy to early childhood, and patients usually have no further recurrence of hyperammonemia with a favorable outcome. This retrospective cohort study reports 18 patients with CA‐VA deficiency caused by homozygosity for a founder mutation, c.59G>A p.(Trp20*) in CA5A. The reported patients show significant intrafamilial and interfamilial variability, and display atypical clinical features. Two adult patients were asymptomatic, 7/18 patients had recurrent hyperammonemia, 7/18 patients developed variable degree of developmental delay, 9/11 patients had hyperCKemia, and 7/18 patients had failure to thrive. Microcephaly was seen in three patients and one patient developed a metabolic stroke. The same variant had been reported already in a single South Asian patient presenting with neonatal hyperammonemic encephalopathy and subsequent development of seizures and developmental delay. This report highlights the limitations of current understanding of the pathomechanisms involved in this disorder, and calls for further evaluation of the possible role of genetic modifiers in this condition