Easy-to-use algorithm would provide faster diagnoses for mucopolysaccharidosis type I and enable patients to receive earlier treatment.

AIM: The aim of this study was to develop an algorithm to prompt early clinical suspicion of mucopolysaccharidosis type I (MPS I). METHODS: An international working group was established in 2016 that comprised 11 experts in paediatrics, rare diseases and inherited metabolic diseases. They reviewed real-world clinical cases, selected key signs or symptoms based on their prevalence and specificity and reached consensus about the algorithm. The algorithm was retrospectively tested. RESULTS: An algorithm was developed. In patients under two years of age, kyphosis or gibbus deformity were the key symptoms that raised clinical suspicion of MPS I and in those over two years they were kyphosis or gibbus deformity, or joint stiffness or contractures without inflammation. The algorithm was tested on 35 cases, comprising 16 Hurler, 10 Hurler-Scheie, and nine Scheie patients. Of these 35 cases, 32 (91%) - 16 Hurler, nine Hurler-Scheie and seven Scheie patients - would have been referred earlier if the algorithm had been used. CONCLUSION: The expert panel developed and tested an algorithm that helps raise clinical suspicion of MPS I and would lead to a more prompt final diagnosis and allow earlier treatment.

International working group identifies need for newborn screening for mucopolysaccharidosis type I but states that existing hurdles must be overcome.

AIM: Mucopolysaccharidosis type I is a lysosomal storage disorder that can result in significant disease burden, disability and premature death, if left untreated. The aim of this review was to elaborate on the diagnosis of mucopolysaccharidosis type I and the pros and cons of newborn screening. METHODS: An international working group was established to discuss ways to improve the early diagnosis of mucopolysaccharidosis type I. It consisted of 13 experts in paediatrics, rare diseases and inherited metabolic diseases from Europe and the Middle East. RESULTS: It is becoming increasingly clearer that the delay between symptom onset and clinical diagnosis is considerable for mucopolysaccharidosis type I and other rare lysosomal storage disorders, despite numerous awareness campaigns since therapies became available. Diagnosis currently depends on recognising the signs and symptoms of the disease. The practice of newborn screening, which is being explored by pilot programmes around the world, enables early diagnosis and consequently early treatment. However, these studies have highlighted numerous new problems and pitfalls that must be faced before newborn screening becomes generally available. CONCLUSION: Newborn screening for mucopolysaccharidosis type I offers the potential for early diagnosis and early pre-symptomatic treatment, but existing hurdles need to be overcome.

Diagnosis and treatment of late-onset Pompe disease in the Middle East and North Africa region: consensus recommendations from an expert group.

BACKGROUND: Pompe disease is a rare autosomal recessive disorder caused by a deficiency of the lysosomal enzyme alpha-glucosidase responsible for degrading glycogen. Late-onset Pompe disease has a complex multisystem phenotype characterized by a range of symptoms. METHODS: An expert panel from the Middle East and North Africa (MENA) region met to create consensus-based guidelines for the diagnosis and treatment of late-onset Pompe disease for the MENA region, where the relative prevalence of Pompe disease is thought to be high but there is a lack of awareness and diagnostic facilities. RESULTS: These guidelines set out practical recommendations and include algorithms for the diagnosis and treatment of late-onset Pompe disease. They detail the ideal diagnostic workup, indicate the patients in whom enzyme replacement therapy should be initiated, and provide guidance on appropriate patient monitoring. CONCLUSIONS: These guidelines will serve to increase awareness of the condition, optimize patient diagnosis and treatment, reduce disease burden, and improve patient outcomes.

Anti-U1RNP-70kD-positive case of neonatal lupus presenting with seizure and incomplete heart block: a case report and literature review.

Neonatal lupus erythematosus (NLE) is an autoimmune disease caused by the transplacental passage of anti-Ro/SS-A and anti-La/SS-B. This can be less commonly seen with U1-ribonucleoprotein (U1RNP). Our patient is a 7-day-old male, who first presented with seizures. In addition, during an electroencephalogram, he was found to have an irregular heart rhythm. Looking further into the history, we found that the mother was aware that she had systemic lupus erythematosus (SLE). However, she had not been followed up with a rheumatologist. The workup for NLE found a negative anti-Ro/SS-A and anti-La/SS-B, with a positive U1RNP-70kD. U1RNP-70kD is a diagnostic test for mixed connective tissue disease in adults, but no research has been done on its significance in NLE. Despite having SLE, the infant's mother did not receive surveillance during her pregnancy, as the current guidelines are tailored for mothers with anti-Ro/SS-A and anti-La/SS-B. As a result, this calls for the extension of these guidelines to include the U1RNP-70kD antibody. In this case, the 70kD subtype of U1RNP was positive, which may have had a role to play in this unusual presentation. However, further research is needed to improve the care of mothers and babies with U1RNP-70kD.

A Case of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis Responsive to Intravenous Immunoglobulin (IVIG) Therapy in a Pediatric Patient.

We present a case of an eight-year-old boy who presented with complaints of headache, blurry vision, and eye pain. Ophthalmological exams and magnetic resonance imaging confirmed the presence of optic neuritis. Initial cerebrospinal fluid analysis was negative for all antibodies (Abs) associated with optic neuritis and other acute demyelinating syndromes, including anti-myelin oligodendrocyte glycoprotein Ab (anti-MOG-Ab). The child was treated with a course of pulse methylprednisolone therapy for five days, with significant improvement in his symptoms. However, the child went on to have a recurrent episode of optic neuritis one month after his initial presentation. Hence, investigations targeting immunological biomarkers were repeated and turned out to be positive for anti-MOG-Abs with elevated titers. The child was diagnosed with MOG-Ab-associated optic neuritis presenting as chronic relapsing inflammatory optic neuropathy (CRION). He was then started on maintenance intravenous immunoglobulin (IVIG) therapy as a disease-modifying therapy, following which he has not had any further relapses over two years.

Gene Therapy for Duchenne Muscular Dystrophy: Unlocking the Opportunities in Countries in the Middle East and Beyond.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder which leads to progressive muscle degeneration and weakness. Most patients die from cardiac or respiratory failure. Gene transfer therapy offers a promising approach to treating this disorder. OBJECTIVE: Given the genetic disease burden, family size, and the high consanguinity rates in the Middle East, our objective is to address current practices and challenges of DMD patient care within two countries in this region, namely the United Arab Emirates and Kuwait, and to outline readiness for gene therapy. METHODS: An expert panel meeting was held to discuss the DMD patient journey, disease awareness, current management of DMD, challenges faced and recommendations for improvement. Opportunities and challenges for gene therapy in both countries were also deliberated. A pre-meeting survey was conducted, and the results were used to guide the discussion during the meeting. RESULTS: DMD awareness is poor resulting in a delay in referral and diagnosis of patients. Awareness and education initiatives, along with an interconnected referral system could improve early diagnosis. Genetic testing is available in both countries although coverage varies. Corticosteroid therapy is the standard of care however there is often a delay in treatment initiation. Patients with DMD should be diagnosed and managed by a multi-disciplinary team in centers of excellence for neuromuscular disorders. Key success factors to support the introduction of gene therapy include education and training, timely and accessible genetic testing and resolution of reimbursement and cost issues. CONCLUSION: There are many challenges facing the management of DMD patients in the United Arab Emirates and Kuwait and most likely other countries within the Middle East. Successful introduction of gene therapy to treat DMD will require careful planning, education, capacity building and prioritization of core initiatives.

Linear Nevus Sebaceous Syndrome in a Child With Infantile Spasms and Focal Cortical Dysplasia.

Linear nevus sebaceous syndrome (LNSS) is a rare neurocutaneous syndrome with important neurological involvement including brain malformation, focal seizures, and developmental delay. We discuss a case with a unique presentation with localization-related infantile spasms and review the clinical and radiological features of this case. To our knowledge, there are no previously reported cases of LNSS with infantile spasms and cortical dysplasia. Therefore, the presented case will make an important contribution to the available knowledge.

Characterization of ETFDH and PHGDH Mutations in a Patient with Mild Glutaric Aciduria Type II and Serine Deficiency.

Glutaric aciduria type II (GA-II) is a rare autosomal recessive disease caused by defects in electron transfer flavoprotein (ETF), ultimately causing insufficiencies in multiple acyl-CoA dehydrogenase (MAD). 3-phosphoglycerate dehydrogenase (3-PHGDH) deficiency, is another rare autosomal disorder that appears due to a defect in the synthesis of L-serine amino acid. Several mutations of ETFDH and PHGDH genes have been associated with different forms of GA-II and serine deficiency, respectively. In this study, we report a unique case of GA-II with serine deficiency using biochemical, genetic, and in silico approaches. The proband of Syrian descent had positive newborn screening (NBS) for GA-II. At two years of age, the patient presented with developmental regression, ataxia, and intractable seizures. Results of amino acid profiling demonstrated extremely low levels of serine. Confirmatory tests for GA-II and whole exome sequencing (WES) were performed to determine the etiology of intractable seizure. Sequencing results indicated a previously reported homozygous missense mutation, c.679 C>A (p.Pro227Thr) in the ETFDH gene and a novel missense homozygous mutation c.1219 T>C (p.Ser407Pro) in the PHGDH gene. In silico tools predicted these mutations as deleterious. Here, the clinical and biochemical investigations indicate that ETFDH:p.Pro227Thr and PHGDH:p.Ser407Pro variants likely underlie the pathogenesis of GA-II and serine deficiency, respectively. This study indicates that two rare autosomal recessive disorders should be considered in consanguineous families, more specifically in those with atypical presentation.

De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873-4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.

Current management of Duchenne muscular dystrophy in the Middle East: expert report.

Aim: Duchenne muscular dystrophy (DMD) is a severe and rare X-linked neuromuscular childhood disorder that results in functional decline, loss of ambulation and early death due to cardiac or respiratory failure. The objective of this paper is to address different aspects of the current management of DMD in the Middle East, north Africa (MENA) region, and to gather experts' recommendations on how to optimally diagnose and treat patients suffering from this disease. Methods: A group of experts (neuromuscular medicine, neuropediatricians and geneticists) convened to discuss the diagnosis and management of DMD in the MENA region. A list of practical statements was prepared by the chair of the meeting to guide the discussions around critical aspects relating to the current and future management of DMD. Results & conclusion: Ideally, DMD management should be a multidisciplinary approach. Nevertheless, few tertiary care hospitals in the region are currently able to provide the full spectrum of medical expertise and services needed by DMD patients. Clinical practice in the region remains heterogeneous. Specific guidelines for diagnosis and treatment are needed in the MENA region to improve outcomes. Disease awareness among the general public and the medical community is lacking. Now that mutation-specific therapies are being developed and more widely studied, general education programs regarding early signs and symptoms, a standardized referral and diagnosis pathway, patient registries and support groups will significantly improve the management of the disease.

Infant botulism type Ba: first culture-confirmed case in the United Arab Emirates.

We report on a 3-month-old girl with culture-confirmed infant botulism caused by a rare double toxin-producing Clostridium botulinum type Ba. This case was not related to honey-feeding. The clinical course was prolonged, with minimal spontaneous improvement at onset, and a period of fluctuating motor weakness and nasogastric feeding dependence afterward. Neurophysiologic studies produced normal results. Human botulism immune globulin was administered empirically on day 23 of presentation, with rapid full recovery. This case highlights the importance of pursuing diagnoses of infant botulism despite normal results of neurophysiologic testing and no history of honey-feeding. Our case also demonstrates a favorable response to human botulism immune globulin, despite the relatively late treatment.

The Changing Face of Infantile Pompe Disease: A Report of Five Patients from the UAE.

OBJECTIVE: We aim to present our experience with infantile Pompe disease with focus on the impact of availability of treatment on awareness, diagnosis, and management of such patients. METHOD: Case - review study of patients diagnosed with infantile Pompe disease and literature search. RESULTS: We identified five cases of infantile Pompe disease. The first was diagnosed by muscle biopsy; all others were diagnosed by enzyme assay on peripheral blood lymphocytes or dried blood spot. There was no determination of the CRIM status on these patients. Two have died at a much later age than the reported median age of death for untreated cases. One died very early at 2 months of age with severe cardiomyopathy and had received only one dose of enzyme replacement therapy (ERT). The remaining two surviving patients are siblings: the younger was diagnosed by prenatal ultrasound screening and started on ERT at 24 h of age; she is the youngest treated patient in our case series. CONCLUSION: The natural history of infantile Pompe disease is changing, so are the challenges of managing these infants in the post- ERT era. Currently, increased awareness and early access to therapy provide the best outcomes and incur the least shift of burden from mortality to morbidity. Disclosure: Authors have received travel support to attend scientific symposiums by Genzyme. WF has also received consulting fees for speaking in a scientific symposium by Genzyme.