Floppy infant syndrome as a first manifestation of LMNA-related congenital muscular dystrophy.

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.

Case Report: Further Delineation of Neurological Symptoms in Young Children Caused by Compound Heterozygous Mutation in the PIEZO2 Gene.

PIEZO2 protein is a unique ion channel that converts mechanical impulses into cellular signals in somatosensory neurons and is involved in various mechanotransduction pathways. The recessive PIEZO2 loss-of-function pathogenic variants are associated with distal arthrogryposis with impaired proprioception and touch (DAIPT). Here we present three new DAIPT patients. The genetic diagnosis was established by exome sequencing and let us to identify 6 novel loss-of-function PIEZO2 variants: four splicing (c.1080+1G>A, c.4092+1G>T, c.6355+1G>T, and c.7613+1G>A), one nonsense (c.6088C>T) and one frameshift variant (c.6175_6191del) for which mosaic variant was identified in proband's mother. All patients presented typical symptoms at birth, with congenital contractures, bilateral hip dislocation/dysplasia, generalized hypotonia, transient feeding and difficulties. Two were afflicted by transient respiratory insufficiency. In all children motor development was severely delayed. In one patient, severe cognitive delay was also observed. Moreover, among the cases described by us there is the youngest diagnosed child to date.

The remarkable phenotypic variability of the p.Arg269HiS variant in the TRPV4 gene.

INTRODUCTION: Mutations in the TRPV4 gene are associated with neuromuscular disorders and skeletal dysplasias, which present a phenotypic overlap. METHODS: Next-generation sequencing and Sanger sequencing were used to analyze the TRPV4 gene. RESULTS: We present 2 Polish families with TRPV4-related disorder harboring the same p.Arg269His mutation. The disease phenotypic expression was extremely variable (from mild scapular winging to severe hypotonia, global weakness, inability to walk unaided, congenital contractures, scoliosis, and respiratory insufficiency), but did not suggest anticipation. The 2 most severely affected patients showed congenital distal contractures of the upper limbs and involvement of cranial nerves (manifesting as facial asymmetry and strabismus). The disease course seemed to be stable, although in later stages it caused respiratory insufficiency and progression of physical disability. DISCUSSION: The phenotypic variability observed in p.Arg269His carriers suggests that an additional modifier or a more complex pathogenic mechanism exists. Muscle Nerve 59:129-133, 2019.