MINPP1-related pontocerebellar hypoplasia (PCH) is a rare neurodevelopmental disorder characterized by microcephaly, profound developmental delay, and a distinct neuroimaging pattern. To date, only 21 patients from 13 unrelated families have been reported. Herein, we describe five patients from four Egyptian families with homozygous MINPP1 variants. All patients presented with global developmental delay, microcephaly, hypotonia, nystagmus, severe motor impairment, seizures, and intellectual disability. Interestingly, all patients exhibited dysmorphic facies, characterized by a high forehead, long philtrum, smooth philtrum, thin upper lip vermilion, broad chin, and low-set ears. Additional variable findings were optic atrophy, strabismus, feeding difficulties, and genital anomalies. Brain MRI showed cerebellar and pontine hypoplasia, thin corpus callosum, cortical atrophic changes, white matter signal, enlarged ventricles, and striking basal ganglia hypoplasia. Exome sequencing identified four MINPP1 variants, including three novel variants (p.Trp68Ter, p.Trp141Ter, and p.Val434_Gln435dup). All variants are localized within functionally critical domains of the protein and were either absent or extremely rare in public databases. Our study increases the number of affected individuals with MINPP1 variants and reinforces the clinical and brain imaging features of the disorder. In addition, the specific facial gestalt noted in our patients along with the basal ganglia changes appear characteristic and might point to the diagnosis of this type of PCH.

Objective: Vaccinia-related kinase 1 (VRK1)-related disease is an extremely rare autosomal recessive disorder primarily affecting the peripheral and/or central nervous system. In this report, we describe the genetic and clinical features of two siblings from a Turkish family presenting with an amyotrophic lateral sclerosis (ALS) phenotype due to a novel homozygous VRK1 mutation, and discuss the broad phenotypic spectrum associated with pathogenic variants in this gene. Methods: We analyzed the demographic data, clinical histories, neurological examinations, laboratory findings, and genetic results of 53 patients, including our cases, derived from 27 different reports. Results: Whole-exome sequencing identified a novel homozygous missense mutation, c.700A > G (p.Asn234Asp), in the VRK1 gene in two affected siblings. The characteristic features of the ALS phenotype included a recessive inheritance pattern, motor deficits with onset in the lower limbs, pyramidal tract signs, and a muscle magnetic resonance imaging (MRI) pattern demonstrating preferential involvement of the posterior compartments of the leg and thigh. The most common phenotypes associated with VRK1 mutations were ALS (18/53, 34%) and distal hereditary motor neuropathy (dHMN) (14/53, 26.4%), followed by pontocerebellar hypoplasia type 1 (7/53, 13.2%), hereditary motor and sensory neuropathy (5/53, 9.4%), autosomal recessive primary microcephaly with brain malformations (4/53, 7.5%), and spastic paraplegia (2/53, 3.8%). The ALS phenotype exhibited a significantly earlier mean age of onset compared to the dHMN phenotype (p = 0.015; 15.3 ± 11.5 and 27 ± 15.5 years, respectively). Conclusion: Our findings highlight the importance of investigating VRK1 mutations in patients with young-onset familial ALS. Furthermore, this report provides a systematic classification of the phenotype definitions associated with VRK1 mutations.

患儿，男，1岁1个月，主诉"转氨酶反复升高6月余"。主要临床表现为整体发育迟缓，精神运动发育落后，小头畸形，肌张力低；实验室检查表现为反复肝功能异常，铜蓝蛋白降低；头颅影像学显示胼胝体薄，脑室系统扩大，脑沟裂池变深、增宽；肝脏病理表现为肝细胞轻度小泡性脂肪变性伴肝纤维化；基因检测结果提示空泡蛋白分选相关蛋白51基因变异。.

Pontocerebellar hypoplasia type 9 (PCH-9) is a very rare autosomal recessive neurodegenerative disorder. Affected infants present early with severe developmental delay, spasticity, with the unique magnetic resonance imaging picture of thin corpus callosum, atrophied pons, and cerebellum. It is caused by loss of function mutations in the AMPD2 gene, encoding for the adenosine monophosphate deaminase enzyme-paralog 2. This gene is expressed in different somatic tissues with high level of expression in cerebellum and its encoded enzyme catalyzes a critical step in de novo biosynthesis of purines and its deficiency in the developing neurons severely affects neuronal differentiation and cell viability. We clinically evaluated an Emirati patient presented with severe developmental and growth delay, as well as corpus callosum agenesis and atrophy of brainstem and cerebellum. We performed exome sequencing, Sanger sequencing, and segregation analysis to identify the genetic cause of the phenotype, followed by in silico and in vitro analysis. We identified the novel variant (NM_004037.9:c.1471G > A) in AMPD2 gene leading to a single amino acid substitution (p.Gly491Arg) in adenosine monophosphate deaminase-2 enzyme. This variant is predicted to be pathogenic using several in silico tools, and resulted in a decrease in the enzyme function in the patient's polymorphonuclear cells by 82% (95% confidence interval: 73.3-91.7%, p  = 0.029) compared with the control. This data establishes that the affected child is affected by PCH-9. Furthermore, we review all reported cases in literature to summarize the main clinical features of this rare disease.

Pontocerebellar hypoplasia (PCH) is currently classified into 16 subgroups. Using mostly next-generation sequencing, pathogenic variants have been identified in as many as 24 PCH-associated genes. PCH type 8 (PCH8) is a rare heterogeneous disorder. Its clinical presentation includes severe development delay, increased muscle tone, microcephaly, and magnetic resonance imaging (MRI) abnormalities such as reduced cerebral white matter, a thin corpus callosum, and brainstem and cerebellar hypoplasia. To date, only two variants in the CHMP1A gene (MIM: 164010), NM_002768.5: c.88 C > T (p.Glu30*) and c.28-13 G > A, have been identified homozygously in seven patients with PCH8 from four families (MIM: 614961). CHMP1A is a subunit of the endosomal sorting complex required for transport III (ESCRT-III), which regulates the formation and release of extracellular vesicles. Biallelic CHMP1A loss of function impairs the ESCRT-III-mediated release of extracellular vesicles, which causes impaired progenitor proliferation in the developing brain. Herein, we report a patient with PCH8 who had a homozygous CHMP1A variant, c.122delA (p.Asn41Metfs*2), which arose from segmental uniparental disomy. Although our patient had similar MRI findings to those of previously reported patients, with no progression, we report some novel neurological and developmental findings that expand our knowledge of the clinical consequences associated with CHMP1A variants.