Cerebral visual impairment: genetic diagnoses and phenotypic associations.

BACKGROUND: Cerebral visual impairment (CVI) is the most common form of paediatric visual impairment in developed countries. CVI can arise from a host of genetic or acquired causes, but there has been limited research to date on CVI in the context of genetic disorders. METHODS: We carried out a retrospective analysis of genotypic and phenotypic data for participants with CVI within the DECIPHER database and 100 000 Genomes Project (100KGP). RESULTS: 158 individuals with CVI were identified across both cohorts. Within this group, pathogenic or likely pathogenic sequence variants in 173 genes were identified. 25 of these genes already have known associations with CVI, while the remaining 148 are candidate genes for this phenotype. Gene ontology analysis of the CVI gene sets from both DECIPHER and 100KGP suggests that CVI has a similar degree of genetic heterogeneity to other neurodevelopmental phenotypes, and a strong association with genetic variants converging on ion channels and receptor functions. Individuals with a monogenic disorder and CVI have a higher frequency of epilepsies and severe neurodisability than individuals with a monogenic disorder but not CVI. CONCLUSION: This study supports the availability of genetic testing for individuals with CVI alongside other neurodevelopmental difficulties. It also supports the availability of ophthalmological screening for individuals with genetic diagnoses linked to CVI. Further studies could elaborate on the links between specific genetic disorders, visual maturation and broader neurodevelopmental characteristics.

Loss of DIAPH1 causes SCBMS, combined immunodeficiency, and mitochondrial dysfunction.

BACKGROUND: Homozygous loss of DIAPH1 results in seizures, cortical blindness, and microcephaly syndrome (SCBMS). We studied 5 Finnish and 2 Omani patients with loss of DIAPH1 presenting with SCBMS, mitochondrial dysfunction, and immunodeficiency. OBJECTIVE: We sought to further characterize phenotypes and disease mechanisms associated with loss of DIAPH1. METHODS: Exome sequencing, genotyping and haplotype analysis, B- and T-cell phenotyping, in vitro lymphocyte stimulation assays, analyses of mitochondrial function, immunofluorescence staining for cytoskeletal proteins and mitochondria, and CRISPR-Cas9 DIAPH1 knockout in heathy donor PBMCs were used. RESULTS: Genetic analyses found all Finnish patients homozygous for a rare DIAPH1 splice-variant (NM_005219:c.684+1G>A) enriched in the Finnish population, and Omani patients homozygous for a previously described pathogenic DIAPH1 frameshift-variant (NM_005219:c.2769delT;p.F923fs). In addition to microcephaly, epilepsy, and cortical blindness characteristic to SCBMS, the patients presented with infection susceptibility due to defective lymphocyte maturation and 3 patients developed B-cell lymphoma. Patients' immunophenotype was characterized by poor lymphocyte activation and proliferation, defective B-cell maturation, and lack of naive T cells. CRISPR-Cas9 knockout of DIAPH1 in PBMCs from healthy donors replicated the T-cell activation defect. Patient-derived peripheral blood T cells exhibited impaired adhesion and inefficient microtubule-organizing center repositioning to the immunologic synapse. The clinical symptoms and laboratory tests also suggested mitochondrial dysfunction. Experiments with immortalized, patient-derived fibroblasts indicated that DIAPH1 affects the amount of complex IV of the mitochondrial respiratory chain. CONCLUSIONS: Our data demonstrate that individuals with SCBMS can have combined immune deficiency and implicate defective cytoskeletal organization and mitochondrial dysfunction in SCBMS pathogenesis.

Characteristic facial features and cortical blindness distinguish the DOCK7-related epileptic encephalopathy.

BACKGROUND: The epileptic encephalopathies display extensive locus and allelic heterogeneity. Biallelic truncating DOCK7 variants were recently reported in five children with early-onset epilepsy, intellectual disability, and cortical blindness, indicating that DOCK7 deficiency causes a specific type of epileptic encephalopathy. METHODS: We identified 23- and 27-year-old siblings with the clinical pattern reported for DOCK7 deficiency, and conducted genome-wide linkage analysis and WES. The consequences of a DOCK7 variant were analyzed on the transcript and protein level in patients' fibroblasts. RESULTS: We identified a novel homozygous DOCK7 frameshift variant, an intragenic tandem duplication of 124-kb, previously missed by CGH array, in adult patients. Patients display atrophy in the occipital lobe and pontine hypoplasia with marked pontobulbar sulcus, and focal atrophy of occasional cerebellar folia is a novel finding. Recognizable dysmorphic features include normo-brachycephaly, narrow forehead, low anterior and posterior hairlines, prominent ears, full cheeks, and long eyelashes. Our patients function on the level of 4-year-old children, never showed signs of regression, and seizures are largely controlled with multi-pharmacotherapy. Studies of patients' fibroblasts showed nonsense-mediated RNA decay and lack of DOCK7 protein. CONCLUSION: DOCK7 deficiency causes a definable clinical entity, a recognizable type of epileptic encephalopathy.

Severe neurodegeneration, progressive cerebral volume loss and diffuse hypomyelination associated with a homozygous frameshift mutation in CSTB.

Mutations of the cystatin B gene (CSTB; OMIM 601145) are known to cause Unverricht-Lundborg disease or progressive myoclonic epilepsy-1A (EPM1A, MIM #254800). Most patients are homozygous for an expanded (>30) dodecamer repeat in the promoter region of CSTB, or are compound heterozygotes for the dodecamer repeat and a point mutation. We report two adolescent sisters born to consanguineous parents of Sri Lankan descent who presented with profound global developmental delay, microcephaly, cortical blindness and axial hypotonia with appendicular hypertonia. Neither sibling ever developed head control, independent sitting or ambulation, and never developed speech. The elder sister had a seizure disorder. Both sisters had profound microcephaly and distinct facial features. On serial brain imaging, they had progressive atrophy of the corpus callosum and supratentorial brain, and diffuse hypomyelination with progressive loss of myelin signal. Exome sequencing revealed both siblings to be homozygous for a c.218dupT (p.His75Serfs*2) mutation in exon 3 of CSTB. The neuroimaging features of our patients are consistent with those observed in Cstb-knockout mice, which supports the hypothesis that disease severity is inversely correlated with the amount of residual functional cystatin B protein.

Novel genetic causes for cerebral visual impairment.

Cerebral visual impairment (CVI) is a major cause of low vision in children due to impairment in projection and/or interpretation of the visual input in the brain. Although acquired causes for CVI are well known, genetic causes underlying CVI are largely unidentified. DNAs of 25 patients with CVI and intellectual disability, but without acquired (eg, perinatal) damage, were investigated by whole-exome sequencing. The data were analyzed for de novo, autosomal-recessive, and X-linked variants, and subsequently classified into known, candidate, or unlikely to be associated with CVI. This classification was based on the Online Mendelian Inheritance in Man database, literature reports, variant characteristics, and functional relevance of the gene. After classification, variants in four genes known to be associated with CVI (AHDC1, NGLY1, NR2F1, PGAP1) in 5 patients (20%) were identified, establishing a conclusive genetic diagnosis for CVI. In addition, in 11 patients (44%) with CVI, variants in one or more candidate genes were identified (ACP6, AMOT, ARHGEF10L, ATP6V1A, DCAF6, DLG4, GABRB2, GRIN1, GRIN2B, KCNQ3, KCTD19, RERE, SLC1A1, SLC25A16, SLC35A2, SOX5, UFSP2, UHMK1, ZFP30). Our findings show that diverse genetic causes underlie CVI, some of which will provide insight into the biology underlying this disease process.

Chromosomal aberrations in cerebral visual impairment.

BACKGROUND: Cerebral visual impairment (CVI) is a disorder in projection and/or interpretation of the visual input in the brain and accounts for 27% of the visually impaired children. AIM: A large cohort of patients with CVI was investigated in order to ascertain the relevance of chromosomal aberrations in the etiology of this disorder. METHODS: 607 patients with CVI and a visual acuity ≤0.3 were assessed for the presence of a chromosomal aberration retrospectively. The observed aberrations were classified for pathogenicity. RESULTS: A total of 98 chromosomal aberrations were found in 79 persons (13%) of the cohort. In nine persons it was not possible to classify the clinical implication of the aberration, due to lack of detailed information. In 70 persons it was possible to classify the aberration for causality: in 41 patients the aberration was associated with CVI, in 16 it was unknown and in 13 the aberration was unlikely to be associated with CVI. For four aberrations, present in 26 patients, the association with CVI has been reported before: trisomy 21, 1p36 deletion syndrome, 17p13.3 deletion syndrome (Miller-Dieker syndrome) and 22q13.3 deletion syndrome (Phelan-McDermid syndrome). The chromosomal aberrations in another 15 patients were for the first time associated with CVI. CONCLUSIONS: Chromosomal aberrations associated with CVI were found in 7% (41/607) of patients, of which 37% (15/41) have not been reported before in association with CVI. Therefore, in patients with CVI chromosomal investigations should be routinely performed to warrant a good clinical diagnosis and counseling.

Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical blindness.

Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709C>T [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(∗)] and c.6232G>T [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes.

Distinctive neurological phenotype associated with partial trisomy of chromosome 16.

We present a case of a live born female infant who presented in early life with a movement disorder, lack of developmental progress and neutropenia. Extensive neuro-metabolic investigation was non-diagnostic. Chromosome analysis of cultured lymphocyte cells showed an abnormal chromosome 16 with additional material noted in the proximal long arm. Additional fluorescence in situ hybridisation studies identified this additional material to represent a duplication of the long arm of chromosome 16 between 16q11.2 and 16q21. There was progressive decline and death by 10 months. Dystonia cortical blindness and neutropenia have not been a reported feature of trisomy 16 to date.

A 3.1-Mb microdeletion of 3p21.31 associated with cortical blindness, cleft lip, CNS abnormalities, and developmental delay.

We report a 3.1-Mb de novo deletion of 3p21.31 in a 3.5-year-old female with cortical blindness, cleft lip, CNS abnormalities, and gross developmental delays. Examination of the region showed approximately 80 genes to be involved in the deletion. Functional analysis of the deleted genes suggests that several of them may be important in normal neuronal maturation and function. Thus, haploinsufficiency of one or more of these genes could potentially contribute to the observed phenotype. Our patient does not have clinical features that overlap completely with either proximal or distal 3p deletions, suggesting that the deletion seen in our patient leads to a distinct clinical phenotype not described previously.

Mice with Ppt1Deltaex4 mutation replicate the INCL phenotype and show an inflammation-associated loss of interneurons.

Infantile Neuronal Ceroid Lipofuscinosis (INCL) results from mutations in the palmitoyl protein thioesterase (PPT1, CLN1) gene and is characterized by dramatic death of cortical neurons. We generated Ppt1Deltaex4 mice by a targeted deletion of exon 4 of the mouse Ppt1 gene. Similar to the clinical phenotype, the homozygous mutants show loss of vision from the age of 8 weeks, seizures after 4 months and paralysis of hind limbs at the age of 5 months. Autopsy revealed a dramatic loss of brain mass and histopathology demonstrated accumulation of autofluorescent granular osmiophilic deposits (GRODS), both characteristic of INCL. At 6 months, the homozygous Ppt1Deltaex4 mice showed a prominent loss of GABAergic interneurons in several brain areas. The transcript profiles of wild-type and mutant mouse brains revealed that most prominent alterations involved parts of the immune response, implicating alterations similar to those of the aging brain and neurodegeneration. These findings make the Ppt1Deltaex4 mouse an interesting model for the inflammation-associated death of interneurons.

3-Hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency.

A boy now 8 years old presented at 21 months of age with developmental arrest, followed by regression, cortical blindness and myoclonic seizures. Urine organic acid analysis revealed 3-hydroxy-2-methylbutyric acid and tiglyglycine; 3-ketothiolase enzyme activity was normal and he was subsequently found to have 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency.

Distinct neuropsychological characteristics in Creutzfeldt-Jakob disease.

OBJECTIVES: To characterise the nature of cognitive change in Creutzfeldt-Jakob disease (CJD). METHODS: Case histories are reported of four patients with sporadic (sCJD) and two with familial CJD (fCJD), with postmortem pathological findings in four cases. The data derived from cognitive examination are examined with respect to the presence or absence of a variety of characteristics to elicit performance profiles across cognitive domains. RESULTS: Three patients with sCJD exhibited clear focal cortical deficits. One patient had visual impairment leading to cortical blindness, associated with posterior hemisphere abnormalities on single photon emission computed tomography (SPECT) imaging; two others had impairments in language, mirrored by left hemisphere SPECT abnormalities. The remaining three patients showed no specific cortical symptomatology. Despite these differences all six patients shared common qualitative characteristics: episodic unresponsiveness, interference effects, and profound verbal and motor perseveration. These common features are interpreted in terms of impaired activation and regulation of neocortex from subcortical structures. Findings from postmortem pathological examination and from the published literature provide converging evidence to implicate a critical role of the thalamus. CONCLUSION: These preliminary findings suggest that sCJD and fCJD may be associated with distinct neuropsychological characteristics.