Vitamin B12 deficiency is a rare entity in the pediatric population. It is often of maternal origin in exclusively breast-fed infants. Its clinical manifestations are multiple and unspecific, encompassing hematological problems and neurodevelopmental consequences. Positive diagnosis and early treatment with vitamin B12 supplementation have a rapidly reversible effect on symptoms. Delayed diagnosis, however, may result in irreversible neurological sequelae. We report the case of a six-month-old infant, admitted with hypotonia and psychomotor regression since the age of four months. The laboratory work-up revealed macrocytic anemia with the presence of megakaryocytes and megaloblasts on the myelogram. Vitamin B12 levels were low, and homocysteine levels were high. A maternal workup showed vitamin B12 deficiency in the mother. A brain MRI showed bilateral frontoparietal cortical atrophy. The patient was put on vitamin B12 supplementation with good evolution. The aim of our work is to shed light on the misleading and varied clinical profile of vitamin B12 deficiency in an exclusively breastfed infant, the serious consequences of maternal vitamin B12 deficiency, and the importance of early diagnosis of this condition.

X-linked myotubular myopathy (XLMTM) is a severe type of congenital skeletal muscle disorder usually presenting at birth requiring extensive resuscitation. While having phenotypic variability, its diagnosis carries a poor prognosis due to high rates of hospitalization and mortality by early infancy. Management of patients with XLMTM should therefore be guided by shared decision-making with parents, considering the severity and progression of the disease, quality of life, and demands on caregivers. We describe a family unit of two half-siblings presenting with the severe neonatal form of XLMTM, with varying prognosis and outcomes. Furthermore, a novel maternally-derived c.343-1G > A variant in intron-5 of the MTM1 gene was identified in this family. Hereby, we propose an algorithm for the management of XLMTM, outlining important considerations during the antenatal and postnatal follow-up period.

UNASSIGNED: Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) syndrome (OMIM #616266) is an autosomal dominant hereditary disease that can lead to the congenital contracture of the limbs and face, hypotonia, and developmental delay. In addition, it may result in growth retardation and present various clinical symptoms, such as brain atrophy, a small pituitary gland, musculoskeletal abnormalities, abnormal breathing, abdominal hernia, and abnormal facial features. Herein, we describe a novel de novo missense genetic variant in the sodium leak channel, non-selective (NALCN) gene that is associated with CLIFAHDD syndrome.
UNASSIGNED: This study describes a patient with varus deformities in both feet, deviation of the ulnar side of the fingers, and severe hypotonia. This patient was subsequently confirmed to have CLIFAHDD syndrome through genetic testing, which also revealed a novel missense de novo genetic variant in the NALCN gene (c.3553G > A, p.Ala1185Thr).
UNASSIGNED: Our findings further enrich the known variant spectrum of the NALCN gene and may expand the range of clinical options for treating NALCN-related disorders.

UNASSIGNED: Okur-Chung neurodevelopmental syndrome (OCNDS; #617062) has been associated with heterozygous mutations in the CSNK2A1 gene (*115440) mapped on the chromosome\'s 20p13 region.
UNASSIGNED: The analysis was performed on a 2-year-old patient who was admitted to our genetic diseases evaluation center by his family with a complaint of hypotonia. We detected a heterozygous NM_177559.3 (CSNK2A1):c.1139_1140dupGG (p.Met381GlyfsTer32) variant in the CSNK2A1 gene from a whole-exome sequence analysis.
UNASSIGNED: The variant that we detected has not been reported in open-access databases to date, so it was evaluated as a novel likely pathogenic variant according to the ACMG-2015 criteria. No variant was detected upon segregation analysis of the patient\'s parents; therefore, the related variant was evaluated as de novo. In this study, we offer the first report of a pathogenic frameshift variant in the CSNK2A1 gene that has a relationship with OCNDS.

Nemaline myopathy is a primary skeletal muscle disorder and one of the congenital myopathies. It can be caused by mutations in at least 12 genes, with the nebulin (NEB) gene being the most common. Here, we present the first case of a neonate with nemaline myopathy from Al-Qunfudhah, Saudi Arabia. A full-term baby boy was delivered via cesarean section due to decreased fetal movement. The baby was covered with a thick meconium stain. He was born with severe distress and underwent an endotracheal tube placement. The baby presented generalized muscle weakness, hypotonia, and areflexia. Examination revealed arthrogryposis, bilateral small chin, undescended testicle, joint deformity, hip dislocation, and clubfoot. Chest examination revealed conducting sound and bilateral equal air entry. Moreover, he experienced bilateral chest wheeze and conducting sound. All laboratory tests were normal, and whole-exome sequencing revealed pathogenic homozygous splice acceptor variant NEB gene c.8889+1G˃A. The patient was first suspected to have spinal muscular atrophy as there was no previous nemaline myopathy case reported from Al-Qunfudhah. However, the typical symptoms and genetic sequencing confirmed his condition. As the society in Al-Qunfudhah is known for consanguinity, as in our case, clinicians should identify other types of myopathy as it is expected to occur in further cases.

BACKGROUND: Peroxisome biogenesis disorders (PBDs) are caused by variants in PEX genes that impair peroxisome function. Zellweger spectrum disorders (ZSDs) are the most severe and common subtype of PBDs, affecting multiple organ systems due to peroxisomal involvement in various metabolic functions. PEX13 gene variants are rare causes of ZSDs, with only 21 cases reported worldwide and none in China.
METHODS: We describe an infant with biochemically and molecularly confirmed ZSDs due to variants in the PEX13 gene, identified by whole exome sequencing and validated by Sanger sequencing. The patient\'s treatment and prognosis were followed up. We also reviewed the literature on previously reported cases with PEX13 variants.
RESULTS: The patient had severe hypotonia, seizures, hepatic dysfunction, failure to thrive, and dysmorphic features. Serum analysis revealed elevated levels of very long-chain fatty acids (VLCFA), phytanic acid, and pipecolic acid. We detected a novel homozygous missense variant c.493G>C (p. Ala165Pro) in the PEX13 gene (NM_002618.3), which caused severe clinical manifestations and was inherited from the consanguineous parents. The patient died at the age of 14 months.
CONCLUSIONS: We report the first case of ZSDs due to the PEX13 variant in China. Our findings broaden the mutational spectrum of the PEX13 gene and indicate that missense variants can lead to severe ZSDs phenotypes, which has implications for genotype-phenotype correlations and genetic counseling.

Transient neonatal myasthenia gravis (TNMG) is a neuromuscular disorder that occurs in infants born from mothers with myasthenia gravis (MG) due to transplacental transfer of antibodies against the acetylcholine receptor. TNMG is a rare form occurring in 10-15% of infants born from mothers with MG. We present a case of a newborn with TNMG with generalized hypotonia and respiratory distress. The newborn shows symptoms of hypotonia, weakened reflexes, poor crying, difficult sucking and potentiated tachydyspnea after 24 hours of birth and needs of assisted mechanical ventilation. Based on the mother\'s positive history of MG and the high titer of mother\'s (8.43nmol/l) and newborn\'s (9.088nmol/l) anti-AChR antibodies, TNMG was diagnosed. The baby was treated with assisted mechanical ventilation and neostig-mine until the anti-AChR antibody titer was negative. Adequate management of the newborn resulted in a positive outcome and evident withdrawal of the symptoms. Although TNMG is one of the rare neuromuscular disorders in newborns that can be treated, a multidisciplinary approach in the management of pregnant women with MG and newborns through timely diagnosis and early appropriate treatment, results in successful resolution of this condition.

Congenital myopathies (CMs) are a group of diseases that primarily affect the muscle fiber, especially the contractile apparatus and the different components that condition its normal functioning. They present as muscle weakness and hypotonia at birth or during the first year of life. Centronuclear CM is characterized by a high incidence of nuclei located centrally and internally in muscle fibers. Clinical case: a 22-year-old male patient with symptoms of muscle weakness since early childhood, with difficulty in performing physical activity according to his age, with the presence of a long face, a waddling gait, and a global decrease in muscle mass. Electromyography was performed, showing a neurogenic pattern and not the expected myopathic one, neuroconduction with reduced amplitude of the motor potential of the peroneal nerve and axonal and myelin damage of the posterior tibial nerves. The microscopic study of the studied striated muscle fragments stained with hematoxylin-eosin and Masson\'s trichrome showed the presence of fibers with central nuclei, diagnosing CM. The patient meets most of the description for CM, with involvement of all striated muscles, although it is important to note the neurogenic pattern present in this case, due to the denervation of damaged muscle fibers, which contain terminal axonal segments. Neuroconduction shows the involvement of motor nerves, but with normal sensory studies, axonal polyneuropathy is unlikely, due to normal sensory potentials. Different pathological findings have been described depending on the mutated gene in this disease, but all coincide with the presence of fibers with central nuclei for diagnosis by this means, which is so important in institutions where it is not possible to carry out genetic studies, and allowing early specific treatment, according to the stage through which the patient passes.

In the process of neuronal development, the protein Purα (encoded by the PURA gene) is essential for neuronal proliferation, dendritic maturation, and the transportation of mRNA to translation sites. Mutations in the PURA gene may alter normal brain development and impair neuronal function, contributing to developmental delays and seizures. Recently, PURA syndrome is described as developmental encephalopathy with or without epilepsy, neonatal hypotonia, feeding difficulties, global developmental delay, and severe intellectual disability. In our study, we aimed to perform a genetic analysis by whole exome sequencing (WES) in a Tunisian patient presented with developmental and epileptic encephalopathy to provide a molecular explanation for the developed phenotype. We collected, also, clinical data of all PURA p.(Phe233del) patients reported yet and compared the clinical features with those of our patient. Results revealed the presence of the known PURA c.697_699del, p.(Phe233del) variant. Our studied case shares some clinical features including hypotonia, feeding difficulties, severe developmental delay, epilepsy, and language delay (nonverbal) but presents a radiological finding undescribed before. Our finding defines and expands the phenotypic and genotypic spectrum of the PURA syndrome supporting the absence of reliable genotype-phenotype correlations and the existence of a highly variable, wide-ranging clinical spectrum.

We report the case of a two-year-old full-term girl of consanguineous Saudi parents, who had a history of poor sucking, hypotonia, and bilateral ptosis, as well as recurrent pediatric intensive care unit (PICU) admissions with apnea and global developmental delay and unremarkable family history. A genetic study was conducted and whole exome sequencing (WES) identified a likely pathogenic homozygous variant c.842C>T p.(Ala281Val) in the SLC25A1 gene. This finding is consistent with the genetic diagnosis of autosomal recessive combined D-2- and L-2-hydroxyglutaric aciduria (D/L-2-HGA). Genetic testing results suggested a diagnosis of congenital myasthenic syndrome (CMS) type 23 [Online Mendelian Inheritance in Man (OMIM) #618197]. CMS is a highly heterogeneous group of neuromuscular junction (NMJ) disorders clinically and genetically and compromises the safety margin required for reliable neuromuscular transmission. Fortunately, we suspected a CMS in our patient, and the initiation of management with pyridostigmine has substantially improved the patient\'s condition.