Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental disorder characterized by malformations of the cerebellum and brainstem, most notably the pathognomonic "molar tooth sign" on magnetic resonance imaging (MRI). Clinical manifestations are heterogeneous and include dysmorphic features, motor and ocular abnormalities, and, in most patients, intellectual developmental disorder (IDD). We describe the case of a nine-year-old boy with prenatal suspicion of ventricular asymmetry and postnatal findings of macrocephaly and facial dysmorphisms. In infancy, he exhibited nystagmus, oculomotor apraxia, irregular breathing, ataxia, and delayed motor milestones; MRI at 18 months revealed cerebellar vermis hypoplasia with a "molar tooth sign," supporting the diagnosis of JS despite the absence of a causative variant in extended genetic testing. Over time, motor and coordination deficits improved with sustained physical and occupational therapy, complemented by school and family support. Cognitive abilities remained within the expected range, although expressive language delay and motor coordination difficulties were present. At the age of eight years, he was diagnosed with attention-deficit/hyperactivity disorder, inattentive subtype, and responded well to methylphenidate, with marked improvements in attention, concentration, handwriting, and academic performance. This case illustrates a milder neurological phenotype of JS with preserved learning abilities, emphasizing the importance of MRI in diagnosis and highlighting the benefit of early individualized rehabilitation and targeted treatment of comorbidities. It also underscores the role of genetic counseling, although no pathogenic variants were identified, reflecting the syndrome's genetic diversity.

Senataxin, an RNA/DNA helicase, is a key protein providing genome stability and one of the best characterized R-loop-binding factors playing an important role in transcription and DNA repair processes. Pathogenic SETX gene variants cause autosomal recessive spinocerebellar ataxia with axonal neuropathy (AOA2, MIM #606002) and autosomal dominant juvenile amyotrophic lateral sclerosis (ALS4, MIM #602433), rare neurodegenerative disorders characterized by juvenile onset of progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, combined upper and lower motor neuron symptoms, and increased serum alpha-fetoprotein (AFP; specific for AOA2). We report two cases of adult patients presenting with cerebellar syndrome, scanned speech, and exercise intolerance which started in the second/third decade of life and were followed by muscle weakness and impaired gait coordination. Whole exome sequencing (WES) was performed to analyze single nucleotide and copy number variants. A decreased coverage of a genomic region of around 16 kb on chromosome 9 (chr9:132,295,852-132,311,876), suggesting a deletion encompassing 5 exons of the SETX gene (exons 11-15, NM_015046.7) was observed. This homozygous SETX (9q34.13) deletion leads to a frame shift and consequently truncation of the helicase domain in the protein. Loss-of-function variants in the SETX gene are known to be pathogenic. Statistical analysis of NGS data from the Polish population identified a few heterozygous carriers, suggesting its region-specific origin.

Oculomotor apraxia (OMA), the clinical manifestation of impaired voluntary initiation of saccadic eye movements, has long been associated with several disorders and genetic mutations in the literature. The present study aims to review all the disorders and genetic mutations associated with OMA reported in the literature. PubMed, MEDLINE, Scopus, EMBASE, and Web of Science databases were systematically searched for related keywords, and related publications from January 2000 to January 2024 were reviewed. All the disorders and genetic mutations presented with OMA in the literature were reported. Clinical manifestations of the congenital disorders- particularly members of autosomal recessive cerebellar ataxias- including Joubert syndrome, ataxia with oculomotor apraxia, ataxia-telangiectasia, and other disorders were discussed, Additionally, the pathophysiology of the genetic mutations in the anatomical pathway of OMA is discussed in this paper. Most of the cases with OMA present this sign early in their disease course; thus, evaluating the possible differential diagnoses can guide clinicians to a more accurate diagnosis. Understanding the spectrum of disorders and clinical manifestations with OMA also provides valuable insights into further clinic-pathological and genetic evaluations of this clinical manifestation.

Background and Objectives: Poretti-Boltshauser syndrome (PBS) is a rare, autosomal recessive disorder caused by pathogenic variants in the LAMA1 gene, resulting in laminin dysfunction. This manifests as a cerebellar malformation with cysts, and patients present with developmental delay and ataxia; however, ocular features are not well-characterised. We aimed to summarise the ocular phenotypes of PBS based on cases reported in the literature. Materials and Methods: A literature search was conducted on Medline, Embase, and PubMed on PBS and its ocular associations. Genetically confirmed PBS cases were reviewed, and genotype-phenotype correlations were investigated. Results: Comprehensive reporting of genotypes and associated systemic and ocular phenotypes was available in 51 patients with PBS, who had 52 distinct variants in LAMA1. Most patients carried homozygous variants. The most common genotype was a c.2935delA homozygous mutation, followed by the c.768+1G>A; c.6701delC compound heterozygous mutation. High myopia was the most common ocular phenotype (n = 39), followed by strabismus (n = 27) and ocular motor apraxia (n = 26). A wide range of other ocular manifestations, including retinal dystrophy, retinal neovascularisation, retinal detachment, strabismus, nystagmus, optic disc and iris hypoplasia, were reported. Patients with the same genotype exhibited variable expressivity. Conclusions: PBS has a broad ocular phenotypic spectrum, and characterisation of this variability is important for making an accurate diagnosis and informing genetic counselling.

Poretti-Boltshauser syndrome (PTBHS) is a neuro-ophthalmological rare genetic disease that has an autosomal recessive inheritance that occurs as a consequence of a mutation in the LAMA1 gene. This gene is important in the development of blood vessels and certain organs, including the cerebellum and the retina. PTBHS is characterized by specific cerebellar abnormalities that manifest in the development of certain clinical features, including cerebellar ataxia, intellectual disability, and delayed language and motor development. In addition to the cerebellar manifestations, retinal abnormalities were noted in patients with PTBHS, such as ocular motor apraxia, severe myopia, strabismus, and retinal dystrophy. In this report, we describe a three-year-old female child diagnosed with PTBHS after assessing and reviewing her clinical presentation and work-up results at Salmaniya Medical Hospital. She presented with nystagmus, poor eye fixation, and delayed gross motor development. The MRI findings were almost subtle, and the diagnosis was confirmed mainly based on the genetic results. LAMA1: c.1243del chr18-7042162TG>T (GRCh37 format) or p.His415Ilefs*78 with transcript ID as NM_005559.4 homozygous mutation was found by whole exome sequencing. Her older sister was also diagnosed with the same disease afterwards by target mutation. Most genetic diseases are difficult to cure, and the management relies mainly on supportive treatment. For that, doctors should pay close attention to the small details in the clinical presentation and investigation findings and always involve a specialized doctor in case any small concern is raised.