Adeno-associated viruses (AAV) are well-suited to serve as gene transfer vectors. Onasemnogene abeparvovec uses AAV9 as virus vector. Previous exposure to wild-type AAVs or placental transfer of maternal AAV antibodies, however, can trigger an immune response to the vector virus which may limit the therapeutic effectiveness of gene transfer and impact safety. We present the case of a female patient with spinal muscular atrophy (SMA) and three survival motor neuron 2 (SMN2) gene copies. The infant had elevated titers of AAV9 antibodies at diagnosis at 9 days of age. Being presymptomatic at diagnosis, it was decided to retest the patient\'s AAV9 antibody titer at two-weekly intervals. Six weeks after initial diagnosis, a titer of 1:12.5 allowed treatment with onasemnogene abeparvovec. The presented case demonstrates that, provided the number of SMN2 gene copies and the absence of symptoms allow, onasemnogene abeparvovec therapy is feasible in patients with initially exclusionary AAV9 antibody titers of >1:50.

Spinal muscular atrophy (SMA) is an autosomal recessive inherited motor neuron disease characterized by progressive muscle weakness due to degeneration and loss of the anterior horn cells in the spinal cord and the brain stem nuclei from foetal life through infancy and childhood. SMA is prevalent in Ghanaian children, though not widely reported. Cases are likely missed or misdiagnosed due to lack of expertise and investigations. Newborn screening is not currently available in Ghana. The management remains supportive as newly approved genetic modifications therapies are currently not available. We present a retrospective folder review of children attending a tertiary pediatric neurology clinic who were diagnosed with SMA and confirmed by molecular genetic testing. Between January 2018 and August 2021, five (5) children from three families had molecular genetic tests confirming their diagnosis of SMA. Three (3) children had SMA I phenotype while 2 had SMA III phenotype. Two (2) of the 3 children with SMA I died from respiratory complications. The last surviving child with SMA I was diagnosed through newborn screening program overseas and received gene modification therapy. Careful history and physical examination remain the best approach to diagnosis as confirmatory genetic testing and supplemental investigations are not readily available. The current management of the children with SMA in Ghana include respiratory care, physiotherapy, and genetic counselling. Genetic modification therapies are currently not available.

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The role of muscle biopsy in the diagnostic workup of floppy infants is controversial. Muscle sampling is invasive, and often, results are not specific. The rapid expansion of genetic approach has made the muscle histopathology analysis less crucial. This study aims to assess the role and efficacy of muscle histopathology in the diagnostic algorithm of hypotonia in early infancy through a retrospective analysis of 197 infants who underwent muscle biopsy in their first 18 months of life. Data analysis revealed that 92/197 (46.7%) of muscle biopsies were non-specific (80) or normal (12), not allowing a specific diagnosis. In 41/197 (20.8%) cases, biopsy suggested a metabolic or mitochondrial myopathy, while in 23/197 cases (11.7%), we found evidence of muscular dystrophy. In 19/197 cases (9.7%), histopathology characteristics of a congenital myopathy were reported. In 22/197 cases (11.7%), the histopathological study indicated presence of a neurogenic damage. Overall, 46 diagnoses were then achieved by oriented genetic tests. Muscle biopsy results were consistent with genetic results in 90% of cases. Diagnostic algorithms for the diagnosis of a floppy infant are largely missing. Muscle biopsy alone can lead to a diagnosis, help the clinician in the choice of a genetic test, or even modify a diagnosis made previously.

LMNA-related congenital muscular dystrophy (L-CMD) is the most severe phenotypic form of skeletal muscle laminopathies. This paper reports clinical presentation of the disease in 15 Polish patients from 13 families with genetically confirmed skeletal muscle laminopathy. In all these patients floppy infant syndrome was the first manifestation of the disease. The genetic diagnosis was established by next generation sequencing (targeted panel or exome; 11 patients) or classic Sanger sequencing (4 patients). In addition to known pathogenic LMNA variants: c.116A > G (p.Asn39Ser), c.745C > T (p.Arg249Trp), c.746G > A (p.Arg249Gln), c.1072G > A (p.Glu358Lys), c.1147G > A (p.Glu383Lys), c.1163G > C (p.Arg388Pro), c.1357C > T (p.Arg453Trp), c.1583C > G (p.Thr528Arg), we have identified three novel ones: c.121C > G (p.Arg41Gly), c.1127A > G (p.Tyr376Cys) and c.1160T > C (p.Leu387Pro). Eleven patients had de novo mutations, 4 - familial. In one family we observed intrafamilial variability of clinical course: severe L-CMD in the male proband, intermediate form in his sister and asymptomatic in their mother. One asymptomatic father had somatic mosaicism. L-CMD should be suspected in children with hypotonia in infancy and delayed motor development, who have poor head control, severe hyperlordosis and unstable and awkward gait. Serum creatine kinase may be high (~1000IU/l). Progression of muscle weakness is fast, leading to early immobilization. In some patients with L-CMD joint contractures can develop with time. MRI shows that the most frequently affected muscles are the serratus anterior, lumbar paraspinal, gluteus, vastus, adductor magnus, hamstrings, medial head of gastrocnemius and soleus. Ultra-rare laminopathies can be a relatively common cause of generalized hypotonia in children. Introduction of wide genome sequencing methods was a breakthrough in diagnostics of diseases with great clinical and genetic variability and allowed approach \"from genotype do phenotype\". However target sequencing of LMNA gene could be considered in selected patients with clinical picture suggestive for laminopathy.

Macrophagic myofasciitis is a rare inflammatory myopathy characterized by peri-fascicular macrophage infiltration without muscle necrosis. Here we report two children presented in the early infancy. Case 1: a 5-month-old girl presented with lack of neck control and floppiness. On examination, generalized hypotonia, absent deep tendon reflexes, and motor power of 2/5 (Medical Research Council grade) were observed. Case 2: a 17-day-old boy presented with poor feeding, tachypnea, and floppiness. On examination, decreased tone in all limbs and power of <2/5 in all limbs with absent reflexes were observed. Routine investigations including serum Creatine phosphokinase of both babies were normal. Muscle biopsy showed features of macrophagic myofasciitis in both infants. Any floppy infant of lower motor neuron type macrophagic myofasciitis should be considered in addition to inherited causes.

Botulism is a rare neuromuscular disorder caused by neurotoxins produced by Clostridium botulinum. The diagnosis of infant botulism may be obscured or delayed, as its presentation is similar to that of infantile neuromuscular disorders. We report the first Korean case of infant botulism in an acute progressive floppy infant with poor sucking and a weak cry. No abnormalities were found in all blood, cerebrospinal fluid, genetic test, nerve conduction study, and imaging studies. A stool-toxin test was finally performed under suspicion of infant botulism, and the result was positive. The patient was immediately treated with heptavalent botulism antitoxin. Follow-up after 3 months showed normal development with a complete resolution of all symptoms. Therefore, clinical suspicion of infant botulism, which is a treatable infantile neuromuscular disease, is essential for early diagnosis and prompt treatment in the differential diagnosis of a floppy infant.

The differential diagnosis of neonatal hypotonia is a complex task, as in newborns hypotonia can be the presenting sign of different underlying causes, including peripheral and central nervous system involvement and genetic and metabolic diseases. This chapter describes how a combined approach, based on the combination of clinical signs and new genetic techniques, can help not only to establish when the hypotonia is related to peripheral involvement but also to achieve an accurate and early diagnosis of the specific neuromuscular diseases with neonatal onset. The early identification of such disorders is important, as this allows early intervention with disease-specific standards of care and, more importantly, because of the possibility to treat some of them, such as spinal muscular atrophy, with therapeutic approaches that have recently become available.

The recessive PIEZO2-associated disease, distal arthrogryposis with impaired proprioception and touch (DAIPT), is characterized by hypotonia, perinatal respiratory distress, significantly delayed motor milestones, and progressive symptoms of distal arthrogryposis and scoliosis. Here, we describe the youngest patient with DAIPT to date, who, at the age of 3.5 years, did not show a single clinical sign of distal arthrogryposis or contractures, but had a history of bilateral clubfoot operations. On the contrary, he presented with some features, not described thus far, such as syringohydromyelia, a small cyst of the spinal cord, moderate microcephaly with premature closure of anterior fontanelle, and spontaneous unilateral patella dislocation at the age of 32 months. Using whole exome sequencing, we identified 2 new different loss-of-function mutations in the PIEZO2 gene in our patient. We also review the phenotypes of all 16 previously published patients with DAIPT, summarize the distinctive clinical features of this rare genetic disorder, and recommend that DAIPT be included in the differential diagnosis of floppy infant. PIEZO2 is a unique ion channel that converts mechanical impulses into cellular signals and is involved in various mechanotransduction pathways. In addition to DAIPT, mutations in PIEZO2 have been described to cause 3 more distinct phenotypes of distal arthrogryposis, which are dominant and associated with gain-of-function mutations. On the contrary, recessive DAIPT is associated with loss-of-function PIEZO2 mutations.

Congenital myopathy is an uncommon neonatal disorder that can manifest in the neonatal period with severe features. Presentation with signs of global hypotonia and respiratory insufficiency are among the classic findings. Rapid diagnosis is essential for medical management and family support. This case study reviews the presentation of hypotonia in the newborn, followed by a path to a diagnosis of nemaline myopathy in the form of an ACTA-1 mutation. This review can aid the clinician in the diagnosis of patients in whom hypotonia is present at birth. Included is a discussion of the incidence, pathophysiology, diagnosis, and management of this devastating disease.