Mitochondrial dysfunction characterized in human induced pluripotent stem cell disease models in MELAS syndrome: A brief summary.

Human induced pluripotent stem cells (hiPSCs) for MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, stroke-like episodes) may allow deeper understanding of how tissue-specific mitochondrial dysfunction result in multi-systemic disease. Here, we summarize how the m.3243G mtDNA mutation affects mitochondrial function in different tissues using iPSC and iPSC-differentiated cell type disease models and what significant findings have been replicated in the independent studies. Through this brief review and with a focus on mitochondrial dysfunction in iPSC-differentiated cell types, namely fibroblast, neuron, and retinal pigment epithelium cells, we aim to bring awareness of hiPSC as a robust mitochondrial disease model even if many unanswered questions remain.

Bilateral choanal stenosis in auriculocondylar syndrome caused by a PLCB4 variant.

Auriculocondylar syndrome (ARCND) is characterized by a distinguished feature of question mark ears and a variation of other minor and major malformations. Monoallelic or biallelic PLCB4 variants have been reported in a subset of affected individuals, referred to as ARCND2. We report on a 3-year-old female with ARCND who presented at birth with question mark ears, micrognathia, and bilateral choanal stenosis that was characterized by difficulty in breathing. She was found to be heterozygous for a novel PLCB4 variant, p.Glu358Gly. Respiratory distress is rare in autosomal dominant ARCND2 and choanal stenosis has not been reported. Our study expands the clinical phenotype of ARCND by adding choanal stenosis as a finding and suggests that PLCB4 play a role in the development of choanal structures.

A founder noncoding GALT variant interfering with splicing causes galactosemia.

Galactosemia is a rare, treatable hereditary disorder of carbohydrate metabolism. We investigated the etiology of decreased GALT enzyme activity in a cohort of newborns referred by the Florida Newborn Screening Program with no detectable GALT variants in diagnostic molecular tests. Six affected individuals from four families with Guatemalan heritage were included. GALT enzyme activity ranged from 20% to 34% of normal. Clinical findings were unremarkable except for speech delay in two children. Via genome sequencing followed by Sanger confirmation we showed that all affected individuals were homozygous for a deep intronic GALT variant, c.1059+390A>G, which segregated as an autosomal recessive trait in all families. The intronic variant disrupts splicing and leads to a premature termination and is associated with a single haplotype flanking GALT, suggesting a founder effect. In conclusion, we present a deep intronic GALT variant leading to a biochemical variant form of galactosemia. This variant remains undiagnosed until it is specifically targeted in molecular testing.

Spastic Diplegia in a Haitian Girl with Angelman Syndrome.

Spastic diplegia, a muscle hypertonia motor syndrome, can occur in conjunction with the characteristic abnormal movement features of Angelman syndrome (AS), a neurodevelopmental disorder with primary features of ataxic gait, happy demeanor, developmental delay, speech impairment, intellectual disability, microcephaly, and seizures. Spastic diplegia is classically associated with cerebral palsy (CP), an umbrella term encompassing developmental delay, abnormal brain magnetic resonance imaging findings, and various types of CP including spastic, ataxic, dyskinetic, and mixed types. We present a 12-year-old Haitian patient of African descent with AS due to a microdeletion involving the entire UBE3A (ubiquitin-protein ligase E3A) gene and spastic diplegia. She was initially given a clinical diagnosis of CP. Cases of AS in patients of African descent have been rarely reported and this case of severe spastic diplegia, unresponsive to medical intervention, reflects a rarely reported presentation of AS in patients of African descent and possibly the first reported case of a Haitian patient with this clinical presentation. Given that deletions are the most common mechanism resulting in AS, this case report provides supportive evidence that chromosome 15q11 deletion-type AS is most frequently associated with spastic diplegia, a more severe motor impairment phenotype in AS.

Autosomal dominant inheritance in a recently described ZMIZ1-related neurodevelopmental disorder: Case report of siblings and an affected parent.

ZMIZ1, zinc finger MIZ-domain containing 1, has recently been described in association with syndromic intellectual disability in which the primary phenotypic features include intellectual disability/developmental delay, seizures, hearing loss, behavioral issues, failure to thrive, and various congenital malformations. Most reported cases have been found to result from de novo mutations except for one set of three siblings in which parental testing could not be performed. With informed consent from the family, we report on a father and his two sons demonstrating autosomal dominant inheritance of a novel pathogenic ZMIZ1 variant, c.1310delC (p.Pro437ArgfsX84), causing this recently described neurodevelopmental syndrome. While they all show syndromic findings along with short stature and intellectual disability, only one child had sensorineural hearing loss. Moreover, severity of intellectual disability and eyelid ptosis were variable among the affected members. Our report demonstrates that phenotypic features of ZMIZ1-related neurodevelopmental syndrome are variable even within the same family and that parental testing to identify a mildly affected parent is needed.