Khalid Al-Thihli

Drug treatment of inborn errors of metabolism: a systematic review

Background The treatment of inborn errors of metabolism (IEM) has seen significant advances over the last decade. Many medicines have been developed and the survival rates of some patients with IEM have improved. Dosages of drugs used for the treatment of various IEM can be obtained from a range of sources but tend to vary among these sources. Moreover, the published dosages are not usually supported by the level of existing evidence, and they are commonly based on personal experience. Methods A literature search was conducted to identify key material published in English in relation to the dosages of medicines used for specific IEM. Textbooks, peer reviewed articles, papers and other journal items were identified. The PubMed and Embase databases were searched for material published since 1947 and 1974, respectively. The medications found and their respective dosages were graded according to their level of evidence, using the grading system of the Oxford Centre for Evidence-Based Medicine. Results 83 medicines used in various IEM were identified. The dosages of 17 medications (21%) had grade 1 level of evidence, 61 (74%) had grade 4, two medications were in level 2 and 3 respectively, and three had grade 5. Conclusions To the best of our knowledge, this is the first review to address this matter and the authors hope that it will serve as a quickly accessible reference for medications used in this important clinical field.

An update on ocular involvement in mucopolysaccharidoses.

Purpose of review The purpose of this review is to provide an update on ocular manifestations of mucopolysaccharidoses (MPS), to highlight diagnostic pitfalls in the evaluation of affected patients, and to briefly review etiopathogenesis, systemic manifestations, and therapeutic interventions in MPS. Recent findings Advances in hematopoietic stem cell transplantation and enzyme replacement therapy for MPS have led to decreased morbidity and increased life-span of patients. Besides other causes, visual impairment because of corneal opacification, retinal degeneration, and optic atrophy remains a common cause of disability in MPS. The application of a standard ophthalmic evaluation protocol may serve as an important diagnostic and disease monitoring tool in patients. Summary Diagnostic delays are not uncommon in patients with MPS. Given the early ocular involvement in MPS, ophthalmologists play a crucial role in early detection and follow-up of patients with MPS. Ophthalmic evaluation can be impeded by corneal opacification and patient cooperation. Altered corneal biomechanics confound intraocular pressure measurements. Recently developed therapies have made early detection increasingly important. Accurate diagnosis of specific MPS subtypes is of paramount importance for initiating appropriate therapy. Combined with advances in supportive care of ocular and systemic manifestations, the prognosis for patients with MPS has vastly improved.

Consanguinity, endogamy and inborn errors of metabolism in Oman: A cross-sectional study

The Sultanate of Oman, like many other Arab countries, has relatively high rates of consanguinity. Reports suggest that the incidence of inborn errors of metabolism (IEM) is also high in Oman. This retrospective cross-sectional study was designed to evaluate the number of patients with IEM being followed at the only two tertiary centers in Oman treating such patients, and to calculate the consanguinity rates among these families. The electronic medical records of all patients were reviewed for demographic and clinical characteristics. A total of 285 patients with IEM were being followed at the 2 centers involved; 162 (56.8%) were male and 123 (43.2%) were female. The history of consanguinity was documented or available for 241 patients: 229 patients (95%) were born to consanguineous parents related as second cousins or closer. First-cousin marriages were reported in 191 families (79.3%), while 31 patients (12.9%) were born to second cousins. The parents of 5 patients (2%) were related as double first cousins, and 2 patients (1%) were born to first cousins once removed. The average coefficient of inbreeding (F) in our study was 0.081. Seventeen patients (6%) had associated comorbid conditions other than IEM. Our study highlights the clinical burden of IEM in Oman and emphasizes the high consanguinity rates among the parents of affected patients.

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.

Rigid Spinal Muscular Dystrophy and Rigid Spine Syndrome Report of 7 Children

Seven children (5 male, 2 female) were seen over the last 16 years with rigid spine syndrome. Six children had rigid spinal muscular dystrophy (selenoprotein N1–related myopathy [SEPN1RM]) and 1 had myopathy associated with rigid spine. The main presenting complaint in all was difficulty in bending the spine. The diagnosis was made on clinical features and imaging of the paraspinal muscles. Muscle histopathology revealed minimal myopathic changes to severe muscle degeneration. Genetic testing, which was only available for the last case, for selenoprotein was negative.

Megalencephalic Leukoencephalopathy with Subcortical Cysts

Megalencephalic leucoencephalopathy with subcortical cysts (MLC) is a genetic degenerative disease of the white matter of the brain. The white matter degenerates and swells, resulting in patients with large head sizes. Cysts are also seen in white matter.1 Children with MLC usually present in the first year of life, though some discrepancy has been reported in their clinical course.1 MLC is a rare neurodegenerative disorder and is reported here for the first time in two siblings in Oman. Two children of consanguineous parents presented in 2004, a girl (A), currently 19 years of age, and a boy (T), currently 11 years. Their main complaint was mild developmental delay and the large head size, the latter noted by the parents during the first year of life, compared to their siblings. The patients gained initial milestones normally but after the first year had difficulty walking. Over time there was an increase in spasticity and weakness of the limbs. At the time of writing, neither child could walk or sit unsupported. The elder sibling (A) had eating difficulties and was fed through a nasogastric tube. She could understand simple commands but had difficulty in speaking. The younger sibling (T) was still able to eat with assistance and had preserved speech. However, he had recently developed gastrooesophageal reflux. Neither sibling had a history of seizures. The other 6 children in the family (3 sons and 3 daughters) were normal; there was no family history of similar or other neurologic conditions in the past two to three generations. In 2004, upon examination at presentation, there was macrocephaly in both patients. The head circumference of patient T was 58 cm at 4 years of age and 59 cm in patient A at 11 years; both measurements are well above the 97th percentile for their ages. The cranial nerves and language were normal. Bipyramdial signs were noted in the upper and lower limbs. There was spasticity in lower limbs with upgoing plantar responses. Although the upper limb muscles were wasted, the power was normal (Medical Research Council grade 5), with brisk deep tendon reflexes. Routine blood and metabolic investigations were normal. Electroencephalography and visual evoked potentials were not performed, as there were no seizures or visual abnormalities. A magnetic resonance imaging (MRI) brain scan revealed bilateral white matter diffuse changes with subcortical cysts [Figure 1]. A diagnosis of MLC was made after consultation with an expert.1,2 Although the diagnosis was clinically certain, there was no genetic confirmation. Recently, MLC1 gene sequencing revealed a homozygous c.432+1G>A mutation. The mutation is predicted to cause aberrant splicing, and it was not found in more than 400 control chromosomes; features which suggest the likely pathogenicity of this mutation.1 Both patients were severely handicapped and on symptomatic treatment only, not yet having developed seizures. Patient A was bedridden and on nasogastric feeding. Figure 1. A to C. A: Axial magnetic resonance images (T2-weighted) of patient T, showing diffuse white matter swelling and hyperintensity (arrows). B: Axial fluid liquid attenuation inversion recovery (FLAIR) image showing subcortical cysts in the frontal region (arrows). ...

TNFRSF1A Gene Causing Tumor Necrosis Factor Receptor-associated Periodic Syndrome in 2 Siblings Displaying Variable Disease Severity and Discordant Heterozygosity for an MEFV E148Q Variant

To the Editor: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal dominant periodic fever syndrome with pan-ethnic distribution caused by mutations in TNFRSF1A 1. To date, over 100 mutations have been described. Among whites, the R92Q mutation is the most frequently observed variant of the TNFRSF1A gene. R92Q is a missense low-penetrance gene mutation that is associated with a mild severity, high rate of spontaneous amelioration, and lower prevalence of amyloidosis compared with structural gene mutation variants2. Despite its relatively high prevalence in the general population, ranging from 1.2% to 4%, only 1 clinically ascertained patient has been described with homozygous R92Q variant3. We hereby describe 2 Omani sisters with TRAPS caused by homozygous R92Q variants in TNFRSF1A . One of the siblings also had associated E148Q variant in the MEFV gene. They both displayed severe phenotype with evident clinical variability. A 12-year-old girl presented at 18 months of age with frequent episodes of high-grade fever lasting between 5 to 14 days occurring … Address correspondence to Dr. R. Abdwani, Child Health Department, Sultan Qaboos University Hospital, P.O. Box 35, P C 123, Al Khod, Sultanate of Oman. E-mail: reemabd{at}hotmail.com

A child with phenylketonuria and focal segmental glomerulosclerosis, the bright side of proteinuria

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism. Phenylalanine hydroxylase is the underlying deficient enzyme. If left untreated, growth failure, microcephaly, global developmental delay, seizures and severe intellectual impairment would characterize the clinical picture of PKU. On the other side of protein homeostasis lies nephrotic syndrome. It is a well-known quantitative defect due to significant proteinuria. Focal segmental glomerulosclerosis (FSGS) is a special congenital variant affecting children and adults. Hereby, we describe a three- year old male child who presented with generalized edema and global developmental delay. Investigations revealed PKU along with FSGS. We assume that congenital nephrosis ameliorated the picture of PKU, and had a salutary effect on the growth and development. Such coexistence between PKU and FSGS hasn’t been described before.

Inborn errors of metabolism in a cohort of pregnancies with non-immune hydrops fetalis: A single center experience

Abstract Objective: The purpose of this study was to determine the frequency of non-immune hydrops fetalis (NIHF) among all pregnancies referred for prenatal care at Sultan Qaboos University Hospital (SQUH) during the study period and to evaluate the underlying etiologies of NIH. Study design: All pregnancies referred to SQUH between February 2014 and December 2015 were identified, and all pregnancies meeting the diagnosis of NIHF were included in this study. All cases of NIHF referred to our center during this period underwent standard systematic diagnostic work-up that included biochemical and molecular studies in addition to the standard investigations for hydrops fetalis. Clinical characteristics and results of the diagnostic work-up were retrospectively reviewed. Results: A total of 3234 pregnancies were referred for prenatal care at SQUH during the study period, and 12 pregnancies were affected by NIHF. An underlying diagnosis was established in nine cases, and the majority of cases (7/9) were caused by inborn errors of metabolism (IEM). These included a novel homozygous variant in the AARS2 gene (5/7) and two cases of galactosialidosis (2/7). Conclusion: IEM was a major cause of NIHF in this cohort. The AARS2 variant accounts for a significant number of cases with NIHF in this cohort of Omani patients.

Rigid Spine Syndrome among Children in Oman

OBJECTIVES Rigidity of the spine is common in adults but is rarely observed in children. The aim of this study was to report on rigid spine syndrome (RSS) among children in Oman. METHODS Data on children diagnosed with RSS were collected consecutively at presentation between 1996 and 2014 at the Sultan Qaboos University Hospital (SQUH) in Muscat, Oman. A diagnosis of RSS was based on the patients history, clinical examination, biochemical investigations, electrophysiological findings, neuro-imaging and muscle biopsy. Atrophy of the paraspinal muscles, particularly the erector spinae, was the diagnostic feature; this was noted using magnetic resonance imaging of the spine. Children with disease onset in the paraspinal muscles were labelled as having primary RSS or rigid spinal muscular dystrophy. Secondary RSS was classified as RSS due to the late involvement of other muscle diseases. RESULTS Over the 18-year period, 12 children were included in the study, with a male-to-female ratio of 9:3. A total of 10 children were found to have primary RSS or rigid spinal muscular dystrophy syndrome while two had secondary RSS. Onset of the disease ranged from birth to 18 months of age. A family history was noted, with two siblings from one family and three siblings from another (n = 5). On examination, children with primary RSS had typical features of severe spine rigidity at onset, with the rest of the neurological examination being normal. CONCLUSION RSS is a rare disease with only 12 reported cases found at SQUH during the study period. Cases of primary RSS should be differentiated from the secondary type.