Consensus-based expert recommendations on the management of MPS IVa and VI in Saudi Arabia.

Background: Mucopolysaccharidosis type IVa (Morquio A syndrome) and mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome) are rare inherited lysosomal storage diseases associated with significant functional impairment and a wide spectrum of debilitating clinical manifestations. These conditions are thought to have higher-than-average prevalence rates in Saudi Arabia due to high rates of consanguineous marriage in the country. There are several unmet needs associated with the management of these diseases in Saudi Arabia.

European Achondroplasia Forum Practical Considerations for Following Adults with Achondroplasia.

Achondroplasia is a lifelong condition requiring lifelong management. There is consensus that infants and children with achondroplasia should be managed by a multidisciplinary team experienced in the condition. However, many people are lost to follow-up after the transition from paediatric to adult care, and there is no standardised approach for management in adults, despite the recent availability of international consensus guidelines.

Novel UBE3B mutations: report of eight patients with Kaufman oculocerebrofacial syndrome with additional clinical findings from a highly consanguineous population.

Biallelic mutations in UBE3B cause Kaufman oculocerebrofacial syndrome (KOS; OMIM 244450) with a wide range of clinical manifestations. In this study, we employed genetic analyses including homozygosity mapping, candidate gene sequencing, whole exome sequencing, and confirmatory Sanger sequencing on eight patients from three unrelated consanguineous families. Our analysis yielded three different novel variants in UBE3B : a missense substitution [NM_130466.

European Achondroplasia Forum guiding principles for the detection and management of foramen magnum stenosis.

Foramen magnum stenosis is a serious, and potentially life-threatening complication of achondroplasia. The foramen magnum is smaller in infants with achondroplasia, compared with the general population, and both restricted growth in the first 2 years and premature closure of skull plate synchondroses can contribute to narrowing. Narrowing of the foramen magnum can lead to compression of the brainstem and spinal cord, and result in sleep apnoea and sudden death.

Real-world evidence in achondroplasia: considerations for a standardized data set.

Background: Collection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes.

Methods: The Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives.

Identification of Variants Underlying Phenylalanine Hydroxylase Deficiency in Saudi Arabia.

Deleterious mutations in the human gene phenylalanine hydroxylase () encoding the phenylalanine hydroxylase enzyme give rise to classic phenylketonuria and hyperphenylalaninemia. Our study was designed to characterize the spectrum of variants in the gene in Saudi patients. We screened a cohort of 72 Saudi patients with clinical and biochemical diagnoses of hyperphenylalaninemia at the largest tertiary care center in Saudi Arabia; the King Faisal Specialist Hospital and Research Center (KFSH&RC), Riyadh.

A Novel Homozygous Founder Variant of in Two Consanguineous Saudi Families.

The genetic architecture of mitochondrial disease continues to expand and currently exceeds more than 350 disease-causing genes. Bi-allelic variants in , also known as Optic Atrophy-10 (OPA10), lead to early-onset recessive optic neuropathy, atrophy, and encephalopathy in the afflicted patients. The gene is known to encode a mitochondrial ubiquinol oxidoreductase that interacts with reticulon 4 and is thought to be a mitochondrial antioxidant NADPH oxidoreductase.

COVID-19 in Unvaccinated patients with inherited metabolic disorders: A single center experience.

Patients with certain inherited metabolic disorders (IMD) are at high risk for metabolic decompensation with exposure to infections. The COVID-19 pandemic has been particularly challenging for health care providers dealing with IMD patients, in view of its unpredictable consequences in these patients. There is limited data in literature on evaluating the impact and the outcome of COVID-19 infection in these patients.

Optimising care and follow-up of adults with achondroplasia.

Background: Achondroplasia is a genetic condition that can cause complications across the lifespan. While complications in childhood are well documented, the natural history of achondroplasia in adults has, until recently, been relatively lacking, and little is known about the care they receive or how they access it. The European Achondroplasia Forum undertook two exploratory surveys, one for healthcare professionals (HCPs) and one for patient advocacy group (PAG) representatives, to gain an understanding of current practices of the transition process of individuals with achondroplasia from paediatric to adult services and how adults perceive their care.

Optimising the diagnosis and referral of achondroplasia in Europe: European Achondroplasia Forum best practice recommendations.

Background: Achondroplasia is the most common form of skeletal dysplasia, with serious comorbidities and complications that may occur from early infancy to adulthood, requiring lifelong management from a multidisciplinary team expert in the condition The European Achondroplasia Forum guiding principles of management highlight the importance of accurate diagnosis and timely referral to a centre specialised in the management of achondroplasia to fully support individuals with achondroplasia and their families, and to appropriately plan management. The European Achondroplasia Forum undertook an exploratory audit of its Steering Committee to ascertain the current situation in Europe and to understand the potential barriers to timely diagnosis and referral.

Results: Diagnosis of achondroplasia was primarily confirmed prenatally (66.

Gonadal mosaicism in GNAO1 causing neurodevelopmental disorder with involuntary movements; two additional variants.

Background: encodes an alpha subunit of the heterotrimeric guanine nucleotide-binding proteins (G proteins). Mutations in result in two clinical phenotypes: Early infantile epileptic encephalopathy 17 (EEIE17-OMIM #615473) and Neurodevelopmental disorder with involuntary movements (NEDIM-OMIM #617493). Both are inherited as autosomal dominant disorders and originate mainly as de novo.

Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of GALNS gene variants and reporting of 68 novel variants.

Mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome) is a rare autosomal recessive lysosomal storage disorder caused by mutations in the N-acetylgalactosamine-6-sulfatase (GALNS) gene. We collected, analyzed, and uniformly summarized all published GALNS gene variants, thus updating the previous mutation review (published in 2014). In addition, new variants were communicated by seven reference laboratories in Europe, the Middle East, Latin America, Asia, and the United States.

The first European consensus on principles of management for achondroplasia.

Achondroplasia is the most common type of skeletal dysplasia, caused by a recurrent pathogenic variant in the fibroblast growth factor receptor 3 (FGFR3). The management of achondroplasia is multifaceted, requiring the involvement of multiple specialties across the life course. There are significant unmet needs associated with achondroplasia and substantial differences in different countries with regard to delivery of care.

SLC25A42-associated mitochondrial encephalomyopathy: Report of additional founder cases and functional characterization of a novel deletion.

SLC25A42 is the main transporter of coenzyme A (CoA) into mitochondria. To date, 15 individuals have been reported to have one of two bi-allelic homozygous missense variants in the as the cause of mitochondrial encephalomyopathy, of which 14 of them were of Saudi origin and share the same founder variant, c.871A > G:p.

Throwing a spotlight on under-recognized manifestations of Gaucher disease: Pulmonary involvement, lymphadenopathy and Gaucheroma.

Background: Gaucher disease (GD) is a rare lysosomal storage disorder classically subdivided into type 1 (non-neuronopathic) GD, and types 2 and 3 (neuronopathic) GD. It is typically characterized by clinical manifestations including anemia, thrombocytopenia, hepatosplenomegaly, bone lesions, and (in more severe forms) neurological impairment. However, less-commonly reported and often under-recognized manifestations exist, which potentially have a significant impact on patient outcomes.

Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.

We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations.

The neuroimaging findings of monocarboxylate transporter 1 deficiency.

Monocarboxylate transporter 1 (MCT1) deficiency was first described in 2014 by Hasselt et al. as a novel genetic cause of recurrent ketoacidosis. Patients present in the first year of life with acute episodes of ketoacidosis triggered by fasting or infections.

Rett Syndrome, a Neurodevelopmental Disorder, Whole-Transcriptome, and Mitochondrial Genome Multiomics Analyses Identify Novel Variations and Disease Pathways.

Rett syndrome (RTT) is a severe neurodevelopmental disorder reported worldwide in diverse populations. RTT is diagnosed primarily in females, with clinical findings manifesting early in life. Despite the variable rates across populations, RTT has an estimated prevalence of ∼1 in 10,000 live female births.

Loss-of-function mutations in UDP-Glucose 6-Dehydrogenase cause recessive developmental epileptic encephalopathy.

Developmental epileptic encephalopathies are devastating disorders characterized by intractable epileptic seizures and developmental delay. Here, we report an allelic series of germline recessive mutations in UGDH in 36 cases from 25 families presenting with epileptic encephalopathy with developmental delay and hypotonia. UGDH encodes an oxidoreductase that converts UDP-glucose to UDP-glucuronic acid, a key component of specific proteoglycans and glycolipids.

Homozygous loss-of-function variants of TASP1, a gene encoding an activator of the histone methyltransferases KMT2A and KMT2D, cause a syndrome of developmental delay, happy demeanor, distinctive facial features, and congenital anomalies.

We report four unrelated children with homozygous loss-of-function variants in TASP1 and an overlapping phenotype comprising developmental delay with hypotonia and microcephaly, feeding difficulties with failure-to-thrive, recurrent respiratory infections, cardiovascular malformations, cryptorchidism, happy demeanor, and distinctive facial features. Two children had a homozygous founder deletion encompassing exons 5-11 of TASP1, the third had a homozygous missense variant, c.701 C>T (p.

The effects of low protein products availability on growth parameters and metabolic control in selected amino acid metabolism disorders patients.

Background: In Saudi Arabia, a diet for life policy has been adopted in the management of amino acid metabolism disorders for years. However, the specially designed low protein products/medical foods - which are one of the important treatment tools - were not available up until several years ago in Saudi Arabia (SA). Our aim was to measure the compliance and quality of life in patients affected with these disorders followed in the metabolic nutrition clinic at King Faisal Specialist Hospital & Research Centre (KFSH&RC), Riyadh, SA.

Spectrum of mutations underlying Propionic acidemia and further insight into a genotype-phenotype correlation for the common mutation in Saudi Arabia.

Propionic acidemia (PA) is an autosomal recessive metabolic disorder. PA is characterized by deficiency of the mitochondrial enzyme propionyl CoA carboxylase (PCC) that results in the accumulation of propionic acid. Alpha and beta subunits of the PCC enzyme are encoded by the and genes, respectively.

Delineating the phenotypic spectrum of hyperphosphatasia with mental retardation syndrome 4 in 14 patients of Middle-Eastern origin.

Hyperphosphatasia with mental retardation syndrome 4 (HPMRS4) is a rare autosomal recessive condition caused by an impairment of glycosylphophatidylinositol biosynthesis. The cardinal features of HPMRS4 include; characteristic facial features, severe intellectual disability and various neurologic abnormalities. We report here detailed clinical, biochemical, and molecular findings of 14 patients clinically suspected to have HPMRS4, from three Middle-Eastern Countries; Saudi Arabia, Qatar, and Oman.