Progressive Dysphagia in Joubert Syndrome: A Report of a Rare Case.

Joubert syndrome is an uncommon, autosomal recessive disorder characterized by abnormal brain development involving the underdevelopment or absence of the cerebellar vermis. The classic clinical features include developmental delays, hypotonia, abnormal eye movements, and hyperpnea. On brain magnetic resonance imaging (MRI), an essential finding for the diagnosis of Joubert syndrome is a cerebellar and brainstem malformation called the molar tooth sign, characterized by a hypoplastic cerebellar vermis with dysplasia of the superior cerebellar peduncles. Here, we describe a case of a two-month-old female with an atypical presentation of Joubert syndrome. Her initial clinical presentation included respiratory distress and concerns for reflux complicated with aspiration pneumonia. Early recognition of clinical and radiologic findings for Joubert syndrome enables an early diagnosis, and therefore timely interventions for improving the child's development and quality of life.

Basilicata-Akhtar Syndrome: Unraveling an Ultrarare Cause of Developmental Delay.

There is still more to learn about the etiology of extremely uncommon developmental disorders. A heterozygous or hemizygous pathogenic variation in male-specific lethal 3 (MSL3) causes the uncommon X-linked condition known as Basilicata-Akhtar syndrome, which is characterized by a global developmental delay that is evident from infancy, feeding difficulties, and muscle hypotonia. Thus far, over 40 cases have been documented. Here, we report the first case of Basilicata-Akhtar syndrome in India. A 3-year-old boy presented with global development delay. Physical examination revealed dysmorphism and hypotonia. After whole exome sequencing, exon 8 of the MSL3 gene on chromosome X showed evidence of a hemizygous single base pair deletion.

PPP2R5E: New gene potentially involved in specific learning disorders and myopathy.

Protein phosphatase 2A (PP2A) is a family of multifunctional enzymatic complexes crucial for cellular signalling, playing a pivotal role in brain function and development. Mutations in specific genes encoding PP2A complexes have been associated with neurodevelopmental disorders with hypotonia and high risk of seizures. In the current work, we present an individual with specific learning problems, motor coordination disorders, hypotonia and behavioural issues. Although whole exome sequencing (WES) did not unveil pathogenic variants in known genes related to these symptoms, a de novo heterozygous variant Glu191Lys was identified within PPP2R5E, encoding the PP2A regulatory subunit B56ε. The novel variant was not observed in the four healthy brothers and was not detected as parental somatic mosaicism. The mutation predicted a change of charge of the mutated amino acid within a conserved LFDSEDPRER motif common to all PPP2R5 B-subunits. Biochemical assays demonstrated a decreased interaction with the PP2A A and C subunits, leading to disturbances in holoenzyme formation, and thus likely, function. For the first time, we report a potential causal link between the observed variant within the PPP2R5E gene and the symptoms manifested in the subject, spanning specific learning problems and motor coordination disorders potentially associated with myopathy.

A Novel Pathogenic TUBA1A Variant in a Croatian Infant Is Linked to a Severe Tubulinopathy with Walker-Warburg-like Features.

Tubulinopathies are associated with malformations of cortical development but not Walker-Warburg Syndrome. Intensive monitoring of a Croatian infant presenting as Walker-Warburg Syndrome in utero began at 21 weeks due to increased growth of cerebral ventricles and foetal biparietal diameter. Monitoring continued until Caesarean delivery at 34 weeks where the infant was eutrophic. Clinical assessment of a progressive neurological disorder of unknown aetiology found a macrocephalic head and markedly hypoplastic genitalia with a micropenis. Neurological examination showed generalized hypotonia with very rare spontaneous movements, hypotonia-induced respiratory insufficiency and ventilator dependence, and generalized myoclonus intensifying during manipulation. With clinical features of hypotonia, lissencephaly, and brain malformations, Walker-Warburg Syndrome was suspected; however, eye anomalies were absent. Genetic trio analysis via whole-exome sequencing only identified a novel de novo mutation in the TUBA1A gene (NM_006009.4:c.848A>G; NP_006000.2:p.His283Arg) in the infant, who died at 2 months of age, as the likely cause. We report a previously unpublished, very rare heterozygous TUBA1A mutation with clinical features of macrocephaly and hypoplastic genitalia which have not previously been associated with the gene. The absence of eye phenotypes or mutations in Walker-Warburg-associated genes confirm this as not a new presentation of Walker-Warburg Syndrome but a novel TUBA1A tubulinopathy for neonatologists to be aware of.

Shear modulus of lower limb muscles in school-aged children with mild hypotonia.

The objective of this study is to compare shear modulus of lower limb muscles between children with hypotonia versus typical development (TD) or developmental disorders associated with altered tone. Nineteen children with mild hypotonia (mean age 9.4 ± 2.3y, 13 male) completed assessment of resting shear modulus of rectus femoris, biceps femoris (BF), tibialis anterior (TA) and gastrocnemius lateralis (GL) at short and long lengths using shear wave elastography. Data was compared with previous data from TD children and a scoping review for children with developmental disorders. Data were collated according to Net-Longitudinal Tension Angle (Net-LTA), which is the muscle length expressed as the net proximal and distal joint angles. Effects of Net-LTA (e.g., short, neutral, long) were examined according to sex, age and body mass index (BMI). In children with hypotonia, shear modulus was: higher at longer versus shorter lengths for four muscles (p < 0.01); correlated with age for BF-short (r = 0.60, p < 0.03) and GL-short (r = -0.54, p < 0.03), with BMI for BF-short (r = 0.71, p < 0.05); and not different between sexes (p > 0.05). The shear modulus values for lower limb muscles for children with mild hypotonia were lower than those for children with Duchenne Muscular Dystrophy (TA-neutral), or Cerebral Palsy (GL-neutral), but not TD children (all four muscles). In conclusion, shear modulus increases with longer muscle length (i.e. higher Net-LTA) in mildly hypotonic children. Children with mild hypotonia have lower shear modulus than children with cerebral palsy and Duchenne muscular dystrophy.

Vitamin B12 Deficiency in Infants With Axial Hypotonia and Psychomotor Regression: Insights From a Moroccan Case Study.

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.

Distal Arthrogryposis with Impaired Proprioception and Touch: A Novel Variant in PIEZO2 Gene in Omani Patients and a Genotype-Phenotype Review from a Single-Center Experience.

Distal arthrogryposis with impaired proprioception and touch (DAIPT) is an autosomal recessive neurogenetic disorder caused by homozygous pathogenic variants in the PIEZO2 gene. Here we present four Omani families with multiple affected members with DAIPT. The genetic diagnosis was established by whole exome sequencing and we identified a previously unreported homozygous missense variant PIEZO2 : c.1591T > C, P.(Trp531Arg) in one family with two affected members. All patients showed clinical manifestation shortly after birth including transient respiratory insufficiency, significant hypotonia, and gross motor developmental delay with preserved cognitive function. The skeletal manifestation including arthrogryposis is more pronounced with age as we saw in our older patient. This case report will be of importance for physicians and genetic counsellors for faster diagnosis and for offering carrier testing for at-risk family members as part of the premarital testing program, which could help in reducing the burden of this disorder.

¿Hipotonía o Flacidez en Rehabilitación? Una Recomendación desde el Origen Etimológico / Hypotonia or Flaccidity in Rehabilitation? A Recommendation from the Etymological Origin

El músculo estriado es un tejido organizado que utiliza la energía química para realizar trabajo físico, el cual se genera a partir de la contracción muscular. Un tono muscular adecuado es necesario para el movimiento eficiente y la realización de actividad básica del cuerpo humano. Las alteraciones del tono muscular en la práctica clínica se clasifican como hipertonía, que es el aumento del tono en los músculos esqueléticos y/o lisos, e hipotonía o flacidez, que es la disminución del tono del músculo esquelético. Los términos hipotonía y flacidez son ampliamente utilizados por los clínicos en la rehabilitación y ambos hacen referencia a una disminución del tono muscular. Este estudio analizó y evaluó el origen etimológico de los términos Hipotonía y Flacidez y la implicancia de sus definiciones. Para determinar el origen etimológico se realizó una búsqueda de los términos en el Diccionario médico-biológico, histórico y etimológico y Diccionario Latino-Español Español-Latino. Para determinar la definición en español se utilizó el Diccionario de Términos Médicos de La Real Academia de Medicina de España; el Diccionario de la Lengua española; el Diccionario Panhispánico de Términos Médicos; la Biblioteca Nacional Médica y la Biblioteca Virtual de Salud de Centro Latinoamericano y del Caribe. Para determinar el uso de estos términos en el ámbito clínico, se realizó una búsqueda en artículos científicos del ámbito neurológico según el criterio de los autores. Por consiguiente, el término más adecuado para referirse a una disminución de tono muscular en rehabilitación sería Hipotonía, de esta manera y según el origen de la lesión, se pueden utilizar los términos Hipotonía central e Hipotonía periférica, si es que están afectadas estructuras asociadas al sistema nervioso central o periférico, respectivamente. Se sugiere que estos términos sean considerados tanto en la práctica clínica como en la docencia cuando existan alteraciones en el sistema nervioso central o periférico que tengan como consecuencia un bajo tono muscular.

SUMMARY: Striated muscle is an organized tissue that utilizes chemical energy to perform physical work, generated through muscle contraction. Proper muscle tone is essential for efficient movement and basic bodily functions. Clinical practice categorizes muscle tone alterations as hypertonia, an increase in tone in skeletal and/or smooth muscles, and hypotonia or flaccidity, a decrease in skeletal muscle tone. These terms are widely used in rehabilitation to denote decreased muscle tone. This study examined the etymological origins of the terms Hypotonia and Flaccidity and their respective definitions. Etymological research utilized the Diccionario Médico- biológico, histórico y etimológico and Diccionario Latino-Español Español-Latino. Spanish definitions were sourced in Diccionario de Términos Médicos de La Real Academia de Medicina de España; Diccionario de la Lengua española; Diccionario Panhispánico de Términos Médicos; Biblioteca Nacional Médica and Biblioteca Virtual de Salud de Centro Latinoamericano y del Caribe. The clinical use of these terms was assessed through neurology articles per authors' criteria. Consequently, Hypotonia is deemed the more suitable term for describing decreased muscle tone in rehabilitation contexts. Depending on the lesion's origin, terms like Central Hypotonia and Peripheral Hypotonia may be used when structures associated with the central or peripheral nervous systems are affected, respectively. It is suggested that these terms be adopted in clinical practice and teaching when addressing alterations in central or peripheral nervous systems resulting in reduced muscle tone.

The phenotypic and genotypic spectrum of individuals with mono- or biallelic ANK3 variants.

ANK3 encodes ankyrin-G, a protein involved in neuronal development and signaling. Alternative splicing gives rise to three ankyrin-G isoforms comprising different domains with distinct expression patterns. Mono- or biallelic ANK3 variants are associated with non-specific syndromic intellectual disability in 14 individuals (seven with monoallelic and seven with biallelic variants). In this study, we describe the clinical features of 13 additional individuals and review the data on a total of 27 individuals (16 individuals with monoallelic and 11 with biallelic ANK3 variants) and demonstrate that the phenotype for biallelic variants is more severe. The phenotypic features include language delay (92%), autism spectrum disorder (76%), intellectual disability (78%), hypotonia (65%), motor delay (68%), attention deficit disorder (ADD) or attention deficit hyperactivity disorder (ADHD) (57%), sleep disturbances (50%), aggressivity/self-injury (37.5%), and epilepsy (35%). A notable phenotypic difference was presence of ataxia in three individuals with biallelic variants, but in none of the individuals with monoallelic variants. While the majority of the monoallelic variants are predicted to result in a truncated protein, biallelic variants are almost exclusively missense. Moreover, mono- and biallelic variants appear to be localized differently across the three different ankyrin-G isoforms, suggesting isoform-specific pathological mechanisms.

X-linked myotubular myopathy in a family of two infant siblings: A case report and review.

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.

Exome sequencing revealed variants in SGCA and SIL1 genes underlying limb girdle muscular dystrophy and Marinesco-Sjögren syndrome patients.

BACKGROUND: Inherited neuromuscular (NMD) and neurodegenerative diseases (NDD) belong to two distinct categories that disturb different components of the nervous system, leading to a variety of different symptoms and clinical manifestations. Both NMD and NDD are a heterogeneous group of genetic conditions. Genetic variations in the SGCA and SIL1 genes have been implicated in causing Limb Girdle Muscular Dystrophy (LGMD), a type of neuromuscular disorder, and Marinesco-Sjögren Syndrome (MSS) which is a neurodegenerative disorder. METHODS: In the present study, we have investigated four patients presenting LGMD and five patients with MSS features. After collecting detailed clinical and family history, necessary laboratory investigations, including estimation of a skeletal muscle marker enzyme serum creatine kinase (CK), nerve conduction study (NCS), electromyography (EMG), echocardiography (Echo), Magnetic resonance imaging (MRI -brain), CT-brain and X-rays were performed. Whole exome followed by Sanger sequencing was employed to search for the disease-causing variants. RESULTS: Physical examination in LGMD patients revealed poor muscle tone and facing difficulty in straightening up from the floor. Clinical history revealed frequent falls and strenuousness in climbing stairs. They started toe-walking in early childhood. Laboratory investigations confirmed elevated CK levels and abnormal NCS and EMG. The MSS patients showed abnormalities in gate and jerking movement, abnormal speech, and strabismus with cataract. MRI-brain showed cerebral atrophy in some MSS patients with elevated CK levels. Whole exome sequencing revealed a nonsense variant [c.C574T, p.(Arg192*)] in the SGCA gene and a frameshift [c.936dupG, p.(Leu313AlaFs*39)] in the SIL1 gene in LGMD and MSS patients, respectively. CONCLUSION: Our study emphasizes the significance of integrating clinical and genetic analyses for precise diagnosis and tailored management strategies in inherited NMD and NDD disorders. To the best of our knowledge, this is the first study documenting SGCA and SIL1 recurrent variants in subcontinent populations with few rare clinical features. The recurrent mutations expanding the global understanding of the mutation's geographic and ethnic distribution and contributing valuable epidemiological data. The study will facilitate genetic counseling for families experiencing similar clinical features, both within Pakistani populations and in other regions.

Spectrum of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3 (MCAHS3) Due to Phosphatidylinositol Glycan Biosynthesis Class T (PIGT) Gene Mutations: A Narrative Review.

Multiple congenital anomalies-hypotonia-seizures syndrome 3 (MCAHS3) results from mutations in the phosphatidylinositol glycan biosynthesis class T (PIGT) gene leading to defects in glycosylphosphatidylinositol transamidase complex (GPI-TA) synthesis. Glycosylphosphatidylinositol serves as an anchor to more than 150 mammalian proteins for attachment on cell surfaces, enabling specific functional properties. Mutations in the PIGT gene result in disruption of this extremely important post-translational protein modification, yielding dysfunctional proteins leading to MCAHS3. An exhaustive literature search was conducted across various electronic databases to reveal only 41 reported cases of MCAHS3 worldwide, emphasizing the rarity of this condition. Multiple congenital anomalies-hypotonia-seizures syndrome 3 has been reported as secondary to 18 different known PIGT variants to date, manifesting as a varying spectrum of craniofacial dysmorphism, developmental delay with epilepsy, cardiac and renal malformations, and unique features in biochemical testing and neuroimaging. This review aims to highlight the constellation of clinical symptoms, diagnostic modalities, and management challenges associated with MCAHS3 cases. It would help determine optimal diagnostic and treatment strategies for newly identified cases and facilitate new research on this rare condition.

Foot Muscle Exercise: A Novel Approach to Improve Motor Functions in Children with Down Syndrome Having Pes Planus - A Randomized Controlled Trial.

OBJECTIVE: The study aimed to determine the efficacy of foot muscle exercises in children with DS having pes planus. METHODS: Forty-seven subjects randomly assigned to foot muscle exercises (study group) or an arch support insole with one-leg balance exercises (control group), thrice weekly intervention for 12-weeks followed by a home program with residual effect assessed after 24-weeks from baseline. RESULTS: The motor functions were significantly improved in both groups (p = 0.00). A positive residual effect was found in the study group for both parameters. Whilst in the control group it failed to give a positive residual effect for GMFM-88, while PBS yielded positive outcomes. The study group showed significantly better results than the control group in comparison. CONCLUSION: The novel finding suggests that the foot muscle exercise has the potential to improve motor functions in children with Down syndrome and it can be used as an alternative therapeutic approach to the conventional method.

Case Report: New presentation of CLIFAHDD syndrome with a novel variant in the NALCN gene and a literature review.

Background: 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. Case description: 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). Conclusions: 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.

A Novel Mutation Diagnosing in Allan-Herndon-Dudley's Syndrome.

Allan-Herndon-Dudley's syndrome (AHDS) is a rare X-linked recessive disease that causes abnormal serum thyroid function tests, severe hypotonia, intellectual disability, and motor deficit due to a mutation in the monocarboxylate transporter 8, which is a thyroid hormone transporter. A 6-month-old male patient presented to our outpatient clinic with a serious hypotonia complaint. With a preliminary diagnosis of AHDS, a molecular genetic examination was performed. The molecular genetic analysis detected a new previously unidentified variant in the SLC16A2 gene. This case has been presented to report the AHDS, which is a rare cause of hypotonia in patients presenting/consulting with severe hypotonia, global developmental delay, and abnormal thyroid function test results. Besides, a novel pathogenic mutation in the SLC16A2 gene has been described in the present article.

D-Bifunctional Protein Deficiency Diagnosis-A Challenge in Low Resource Settings: Case Report and Review of the Literature.

D-bifunctional protein deficiency (D-BPD) is a rare, autosomal recessive peroxisomal disorder that affects the breakdown of long-chain fatty acids. Patients with D-BPD typically present during the neonatal period with hypotonia, seizures, and facial dysmorphism, followed by severe developmental delay and early mortality. While some patients have survived past two years of age, the detectable enzyme activity in these rare cases was likely a contributing factor. We report a D-BPD case and comment on challenges faced in diagnosis based on a narrative literature review. An overview of Romania's first patient diagnosed with D-BPD is provided, including clinical presentation, imaging, biochemical, molecular data, and clinical course. Establishing a diagnosis can be challenging, as the clinical picture is often incomplete or similar to many other conditions. Our patient was diagnosed with type I D-BPD based on whole-exome sequencing (WES) results revealing a pathogenic frameshift variant of the HSD17B4 gene, c788del, p(Pro263GInfs*2), previously identified in another D-BPD patient. WES also identified a variant of the SUOX gene with unclear significance. We advocate for using molecular diagnosis in critically ill newborns and infants to improve care, reduce healthcare costs, and allow for familial counseling.

Mitochondrial phosphate-carrier deficiency mimicking infantile-onset Pompe disease.

The mitochondrial phosphate carrier is critical for adenosine triphosphate synthesis by serving as the primary means for mitochondrial phosphate import across the inner membrane. Variants in the SLC25A3 gene coding mitochondrial phosphate carrier lead to failure in inorganic phosphate transport across mitochondria. The critical dependence on mitochondria as an energy source is especially evident in tissues with high-energy demands such as the heart, muscle; defects in the mitochondrial energy production machinery underlie a wide range of primary mitochondrial disorders that present with cardiac and muscle diseases. The characteristic clinical picture of a prominent early-onset hypertrophic cardiomyopathy and lactic acidosis may be an indication for analysis of the SLC25A3 gene. Here, described a patient with suspicion of infantile Pompe disease due to involvement of heart and muscle and high-level of plasma creatinine kinase but finally diagnosed mitochondrial phosphate-carrier deficiency.

A novel AP1S2 variant causing leaky splicing in X-linked intellectual disability: Further delineation and intrafamilial variability.

Pettigrew syndrome (PGS), an X-linked intellectual disability (XLID), is caused by mutations in the AP1S2 gene. Herein, we described a Thai family with six patients who had severe-to-profound intellectual impairment, limited verbal communication, and varying degrees of limb spasticity. One patient had a unilateral cataract. We demonstrated facial evolution over time, namely coarse facies, long faces, and thick lip vermilions. We identified a novel AP1S2 variant, c.1-2A>G. The mRNA analysis revealed that the variant resulted in splicing defects with leaky splicing, yielding two distinct aberrant transcripts, one of which likely resulting in the mutant protein lacking the first 44 amino acids whereas the other possibly leading to no production of the protein. By performing a literature review, we found 51 patients and 11 AP1S2 pathogenic alleles described and that all the variants were loss-of-function alleles. The severity of ID in Pettigrew syndrome is mostly severe-to-profound (54.8%), followed by moderate (26.2%) and mild. Progressive spasticity was noted in multiple patients. In summary, leaky splicing found in the present family was likely related to the intrafamilial clinical variability. Our data also support the previous notion of variable expression and neuroprogressive nature of the disorder.

Nemaline Myopathy in a Hypotonic Neonate: Diagnostic Approach for Early Detection and Management.

Neonatal hypotonia presents with low muscle tone and an array of symptoms that vary depending on the etiology. The differential diagnosis for this condition is complex. It is crucial to exclude life-threatening causes before following a diagnostic algorithm and performing additional tests. Given the wide range of clinical symptoms and etiologies for neonatal hypotonia, rapid genetic testing has the potential to expedite diagnosis, reduce invasive testing such as muscle biopsy, reduce hospital stays, and guide condition management.  A four-week-old girl was admitted to the emergency department (ED) with a one-day history of lethargy, poor feeding, congestion, cough, and hypoxemia. Given positive rhino-enterovirus testing and high inflammatory markers, antibiotics were administered. Imaging, venous blood gas, and blood cultures were negative, and the patient was admitted to the pediatric intensive care unit (PICU) for hypoxemia. After speech-language pathology (SLP) and occupational therapy (OT) evaluation, weak orofacial muscles and feeding issues resulted in a nasogastric tube placement. A swallow study revealed decreased pharyngeal contraction and post-swallow liquid residue. Laryngoscopy showed mild laryngomalacia and dysphagia with aspiration. Genetic testing identified an ACTA1 mutation and confirmed nemaline myopathy (NM). The patient's oxygen levels dropped further during sleep, resulting in diagnoses of severe obstructive and moderate-severe central sleep apnea. Treatment included oxygen therapy, SLP, physical therapy, albuterol, and cough assists. After discharge, the patient was frequently re-admitted with chronic respiratory failure and bronchiolitis and later had gastrostomy and tracheostomy tubes inserted.  This specific case highlights the importance of implementing a diagnostic algorithm for neonatal hypotonia. It is also important for physicians, especially emergency medicine (EM) providers, to first exclude infection, sepsis, and cardiac and respiratory organ failure before looking into other tests. Then, physicians should evaluate for more rare etiologies. In this patient's case, the hypotonia was due to a rare genetic disease, nemaline myopathy, and a multidisciplinary approach was used for this patient's care.

Discovery of a novel homozygous SOD1 truncating variant bolsters infantile SOD1 deficiency syndrome.

OBJECTIVE: Superoxide dismutase 1 (SOD1) is an important antioxidant enzyme whose main function is to neutralise superoxide free radicals in the cytoplasm. Heterozygous variants in SOD1 are responsible for a substantial percentage of familial amyotrophic lateral sclerosis (ALS) cases. Recently, several reports have shown that biallelic loss of SOD1 function results in a novel phenotype called infantile SOD1 deficiency syndrome, which is consistent with a recessive pattern of inheritance and can be distinguished from typical (adult-onset) ALS. METHODS: We documented detailed family histories and clinical data, followed by whole-exome sequencing and family co-segregation analysis through Sanger sequencing. To facilitate comparisons, relevant data from fifteen previously reported patients with SOD1-related neurodevelopmental disorders were included. RESULTS: This study presents a new Turkish family with two affected children exhibiting severe delayed motor development, infancy-onset loss of motor skills, axial hypotonia, tetraspasticity, and impaired cognitive functions. Genetic analysis revealed a novel homozygous frameshift variant in SOD1 (c.248dupG [p.Asp84Argfs*8]), with computational biochemical studies shedding light on the mechanistic aspects of SOD1 dysfunction. CONCLUSIONS: Our findings contribute an affirmative report of a fourth biallelic variant resulting in a severe clinical phenotype, reminiscent of those induced by previously identified homozygous loss-of-function SOD1 variants. This research not only advances our understanding of the pathogenesis of this debilitating neurological syndrome but also aligns with ongoing intensive efforts to comprehend and address SOD1-linked ALS.