Diagnostic genome sequencing improves diagnostic yield: a prospective single-centre study in 1000 patients with inherited eye diseases.

PURPOSE: Genome sequencing (GS) is expected to reduce the diagnostic gap in rare disease genetics. We aimed to evaluate a scalable framework for genome-based analyses 'beyond the exome' in regular care of patients with inherited retinal degeneration (IRD) or inherited optic neuropathy (ION). METHODS: PCR-free short-read GS was performed on 1000 consecutive probands with IRD/ION in routine diagnostics. Complementary whole-blood RNA-sequencing (RNA-seq) was done in a subset of 74 patients. An open-source bioinformatics analysis pipeline was optimised for structural variant (SV) calling and combined RNA/DNA variation interpretation. RESULTS: A definite genetic diagnosis was established in 57.4% of cases. For another 16.7%, variants of uncertain significance were identified in known IRD/ION genes, while the underlying genetic cause remained unresolved in 25.9%. SVs or alterations in non-coding genomic regions made up for 12.7% of the observed variants. The RNA-seq studies supported the classification of two unclear variants. CONCLUSION: GS is feasible in clinical practice and reliably identifies causal variants in a substantial proportion of individuals. GS extends the diagnostic yield to rare non-coding variants and enables precise determination of SVs. The added diagnostic value of RNA-seq is limited by low expression levels of the major IRD disease genes in blood.

Novel likely pathogenic variants in TMEM126A identified in non-syndromic autosomal recessive optic atrophy: two case reports.

BACKGROUND: Reports on autosomal recessive optic atrophy (arOA) are sparse and so far, only one gene has been specifically associated with non-syndromic arOA, namely TMEM126A. To date, all reports of pathogenic TMEM126A variants are from affected individuals of Maghrebian origin, who all carry an identical nonsense variant. Here we report two novel variants in the TMEM126A gene from non-Maghreb individuals, both found in affected individuals with an arOA phenotype. CASE PRESENTATION: We report three affected individuals from two families. The proband of family A, a 24-year-old Turkish woman, was diagnosed with visual loss in early childhood but a diagnosis of optic atrophy was only made at 14 years. A diagnostic gene panel revealed a splice donor variant (c.86 + 2 T > C) in homozygous state in the TMEM126A gene. Analysis of this variant based on RNA from whole blood revealed a single aberrant transcript lacking exon 2, presumably representing a functional null allele. Two siblings from family B, a 16-year old Iraqi girl and her 14-year old brother, were diagnosed with optic atrophy in early childhood. A missense variant p.(S36 L) in the TMEM126A gene was identified in homozygous state in a gene panel-based diagnostic setting in both siblings. This missense variant is ultra rare in the general population, affects a highly evolutionarily conserved amino acid and segregates with the disease within the family. The three probands reported in this study had a relatively mild clinical course without any evidence of a syndromic (e.g. neurological) comorbidity, which is in line with previous studies. CONCLUSIONS: We provide additional evidence for the implication of biallelic pathogenic TMEM126A variants in arOA. Our findings extend both the mutational spectrum and geographic presence of TMEM126A in arOA. Screening of the entire gene should be considered in affected individuals presenting with features resembling arOA and also from non-Maghrebian descent.

ARSACS as a Worldwide Disease: Novel SACS Mutations Identified in a Consanguineous Family from the Remote Tribal Jammu and Kashmir Region in India.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare neurodegenerative disorder characterized by the triad of early-onset cerebellar ataxia, peripheral sensorimotor neuropathy, and lower limb spasticity. Here, we present a 28-year-old male patient with symptoms of ARSACS and mild intellectual disability from a consanguineous family of tribal J&K, India. Whole exome sequencing unraveled a novel homozygous frameshift SACS mutation (Cys2869ValfsTer15) in the patient. In addition to the well-established ARSACS imaging features, MRI revealed T2 hyperintense rim around the thalami ("bithalamic stripes") demonstrating that this feature might serve as an additional supportive diagnostic imaging marker for ARSACS. Moreover, retinal nerve fiber layer thickening which has recently been proposed as a diagnostic biomarker for ARSACS was present on routine optic coherence tomography (OCT) also in this patient, indicating that it might indeed present a relatively universal diagnostic biomarker for ARSACS. In sum, our findings extend the geographical distribution of ARSACS to even very remote tribal regions in Asia (such as the Rajouri region of J&K, India) and extend the mutational and imaging spectrum of ARSACS. They provide further support that brain imaging and OCT markers might serve as diagnostic biomarkers for ARSACS in patients with novel SACS mutations, applicable even in remote regions of the world to identify and confirm ARSACS disease.

Full-field electroretinography, visual acuity and visual fields in Usher syndrome: a multicentre European study.

PURPOSE: Usher syndrome (USH) is a multisensory deficiency involving vision, hearing and the vestibular system. The purpose of this study is to report on the functional data (i.e. electroretinography, visual fields, visual acuity) of patients with retinitis pigmentosa (RP) due to Usher syndrome that were collected in a multicentre European study (TREATRUSH). METHODS: A total of 268 genetically confirmed USH patients underwent electrophysiological examinations in the context of multimodal ophthalmological examination in the study (75 USH1, 189 USH2 and four USH3). Full-field electroretinography (ERG) was performed according to ISCEV standards, visual field determination was carried out with either the Octopus or Goldmann perimeters and visual acuity was examined with either ETDRS or Snellen charts. The data were compared between USH subtypes (USH1/USH2/USH3) and correlated with age. RESULTS: Visual acuity decreases significantly with age for both USH1 and USH2 (p < 0.001), without a difference between the two cohorts. When corrected for age, the preserved kinetic visual field was significantly larger in USH2 than in USH1 (p = 0.04). Furthermore, the preserved kinetic visual field area showed a significant decrease with age (based on an exponential fit) in both USH1 and USH2 (p < 0.001). In USH1 patients, however, the visual field was already vastly reduced at an early age. The ERG results were abnormal in all patients. Detectable data for scotopic ERG were obtained from nine patients, and data of photopic ERG were obtained from 24 patients, without a difference between USH1 and USH2 subtypes. CONCLUSIONS: There are differences in the phenotypes of RP in USH subtypes, most visible in the progression of visual fields between USH1 and USH2. The perimetric reduction occurs earlier in USH1 than in USH2. In both subtypes, visual acuity decreases significantly with age and the ERG is not detectable already at early ages.

[Optic Disc Drusen]. / Drusenpapillen.

With a prevalence of about 2%, drusen papillae are a very frequent papilla anomaly. The pathological mechanism of their origin is unclear. If the ophthalmoscopic image is not unambiguous, it may be helpful to examine relatives, as the heredity exhibits irregular dominance. Calcium deposits are common and can be detected by sonography. Glands can also be detected by OCT in section and by autofluorescence. Precise funduscopy and documentation of the findings and follow-up are very important. There is no therapy for drusen papillae. The internal ocular pressure must be regularly controlled, as glaucoma cannot be identified from the papilla findings. The risk is increased of anterior ischaemia of the optical nerve.

PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum.

Boucher-Neuhäuser and Gordon Holmes syndromes are clinical syndromes defined by early-onset ataxia and hypogonadism plus chorioretinal dystrophy (Boucher-Neuhäuser syndrome) or brisk reflexes (Gordon Holmes syndrome). Here we uncover the genetic basis of these two syndromes, demonstrating that both clinically distinct entities are allelic for recessive mutations in the gene PNPLA6. In five of seven Boucher-Neuhäuser syndrome/Gordon Holmes syndrome families, we identified nine rare conserved and damaging mutations by applying whole exome sequencing. Further, by dissecting the complex clinical presentation of Boucher-Neuhäuser syndrome and Gordon Holmes syndrome into its neurological system components, we set out to analyse an additional 538 exomes from families with ataxia (with and without hypogonadism), pure and complex hereditary spastic paraplegia, and Charcot-Marie-Tooth disease type 2. We identified four additional PNPLA6 mutations in spastic ataxia and hereditary spastic paraplegia families, revealing that Boucher-Neuhäuser and Gordon Holmes syndromes in fact represent phenotypic clusters on a spectrum of neurodegenerative diseases caused by mutations in PNPLA6. Structural analysis indicates that the majority of mutations falls in the C-terminal phospholipid esterase domain and likely inhibits the catalytic activity of PNPLA6, which provides the precursor for biosynthesis of the neurotransmitter acetylcholine. Our findings show that PNPLA6 influences a manifold of neuronal systems, from the retina to the cerebellum, upper and lower motor neurons and the neuroendocrine system, with damage of this protein causing an extraordinarily broad continuous spectrum of associated neurodegenerative disease.

Assessment of functional and morphometric endpoints in patients with non-arteritic anterior ischemic optic neuropathy (NAION).

BACKGROUND: The primary objective of this bi-center explorative pilot study was the quantitative assessment of visual field defects and retinal nerve fiber layer thickness (RNFT) over 6 months in patients with acute non-arteritic anterior ischemic optic neuropathy (NAION), in order to elucidate the natural course of NAION and provide a reference dataset for future treatment studies. METHODS: 16 patients (age 41-80 years, nine males, seven females) suffering from acute NAION and presenting within 7 days after onset of symptoms were included in this study. The following examinations were carried out at the initial visit (month 0) and at months 2, 4 and 6: entire (90°) visual field examination with automated static white-on-white perimetry, quantified by mean defect (MD); peripapillary retinal nerve fiber layer thickness (RNFT) measurement with spectral domain optical coherence tomography (SD-OCT); assessment of distant best correct visual acuity (D-BCVA) and a quantification of the relative afferent pupillary defect (RAPD) using the swinging flashlight test with neutral density filters. Perimetric Mean Defect (MD) and RNFT values were each compared between the consecutive visits using the non-parametric Friedman test. RESULTS: The initial MD was 6.2 dB (IQR 5.0-7.4) without significant changes further on. RNFT was 183 µm (IQR 148-252) initially, decreased significantly at month 2 (78 µm (IQR 71-93) and further at month 4 (64 µm (IQR 58-74) and 6 (61 µm (IQR 52-81), Friedman test, p < 0.001). Initially, RNFT was above normal limits (due to swelling) in 15/16 patients; at month 2 it was below normal limits in 13/16 patients, at month 4 in 12/13 patients and at month 6 in 9/10 patients. 7/16 patients exhibited segmental swelling of the optic disc, whereas the entire circumference of the optic disc showed RNFL thickening in 9/16 patients. CONCLUSION: Functional deficits were present directly after onset of NAION and did not change relevantly further on. Morphological changes comprise severe swelling after onset of NAION, which rapidly turns into atrophy. Already after 2 months more than 80 % of the patients showed a RNFT below normal limits. Progressive RNFL thinning between month 2 and month 4 suggests ongoing atrophy, whereas a stable morphologic end point is reached after month 4.

Comprehensive analysis of two hotspot codons in the TUBB4B gene and associated phenotypes.

Our purpose was to elucidate the genotype and ophthalmological and audiological phenotype in TUBB4B-associated inherited retinal dystrophy (IRD) and sensorineural hearing loss (SNHL), and to model the effects of all possible amino acid substitutions at the hotspot codons Arg390 and Arg391. Six patients from five families with heterozygous missense variants in TUBB4B were included in this observational study. Ophthalmological testing included best-corrected visual acuity, fundus examination, optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ERG). Audiological examination included pure-tone and speech audiometry in adult patients and auditory brainstem response testing in a child. Genetic testing was performed by disease gene panel analysis based on genome sequencing. The molecular consequences of the substitutions of residues 390 and 391 on TUBB4B and its interaction with α-tubulin were predicted in silico on its three-dimensional structure obtained by homology modelling. Two independent patients had amino acid exchanges at position 391 (p.(Arg391His) or p.(Arg391Cys)) of the TUBB4B protein. Both had a distinct IRD phenotype with peripheral round yellowish lesions with pigmented spots and mild or moderate SNHL, respectively. Yet the phenotype was milder with a sectorial pattern of bone spicules in one patient, likely due to a genetically confirmed mosaicism for p.(Arg391His). Three patients were heterozygous for an amino acid exchange at position 390 (p.(Arg390Gln) or p.(Arg390Trp)) and presented with another distinct retinal phenotype with well demarcated pericentral retinitis pigmentosa. All showed SNHL ranging from mild to severe. One additional patient showed a variant distinct from codon 390 or 391 (p.(Tyr310His)), and presented with congenital profound hearing loss and reduced responses in ERG. Variants at codon positions 390 and 391 were predicted to decrease the structural stability of TUBB4B and its complex with α-tubulin, as well as the complex affinity. In conclusion, the twofold larger reduction in heterodimer affinity exhibited by Arg391 substitutions suggested an association with the more severe retinal phenotype, compared to the substitution at Arg390.

Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia.

Mutations in the gene encoding the catalytic subunit of the cone photoreceptor phosphodiesterase (PDE6C) have been recently reported in patients with autosomal recessive inherited achromatopsia (ACHM) and early-onset cone photoreceptor dysfunction. Here we present the results of a comprehensive study on PDE6C mutations including the mutation spectrum, its prevalence in a large cohort of ACHM/cone dysfunction patients, the clinical phenotype and the functional characterization of mutant PDE6C proteins. Twelve affected patients from seven independent families segregating PDE6C mutations were identified in our total patient cohort of 492 independent families. Eleven different PDE6C mutations were found including two nonsense mutations, three mutations affecting transcript splicing as shown by minigene assays, one 1 bp-insertion and five missense mutations. We also performed a detailed functional characterization of six missense mutations applying the baculovirus system to express recombinant mutant and wildtype chimeric PDE6C/PDE5 proteins in Sf9 insect cells. Purified proteins were analyzed using Western blotting, phosphodiesterase (PDE) activity measurements as well as inhibition assays by zaprinast and Pγ. Four of the six PDE6C missense mutations led to baseline PDE activities and most likely represent functional null alleles. For two mutations, p.E790K and p.Y323N, we observed reduction in PDE activity of approximately 60% and 80%, respectively. We also observed differences for Pγ inhibition. The p.E790K mutant, with an IC50 value of 2.7 nm is 20.7-fold more sensitive for Pγ inhibition, whereas the p.Y323N mutant with an IC50 of 158 nm is 3-fold less sensitive when compared with the wildtype control.

Artificial vision with wirelessly powered subretinal electronic implant alpha-IMS.

This study aims at substituting the essential functions of photoreceptors in patients who are blind owing to untreatable forms of hereditary retinal degenerations. A microelectronic neuroprosthetic device, powered via transdermal inductive transmission, carrying 1500 independent microphotodiode-amplifier-electrode elements on a 9 mm(2) chip, was subretinally implanted in nine blind patients. Light perception (8/9), light localization (7/9), motion detection (5/9, angular speed up to 35 deg s(-1)), grating acuity measurement (6/9, up to 3.3 cycles per degree) and visual acuity measurement with Landolt C-rings (2/9) up to Snellen visual acuity of 20/546 (corresponding to decimal 0.037° or corresponding to 1.43 logMAR (minimum angle of resolution)) were restored via the subretinal implant. Additionally, the identification, localization and discrimination of objects improved significantly (n = 8; p < 0.05 for each subtest) in repeated tests over a nine-month period. Three subjects were able to read letters spontaneously and one subject was able to read letters after training in an alternative-force choice test. Five subjects reported implant-mediated visual perceptions in daily life within a field of 15° of visual angle. Control tests were performed each time with the implant's power source switched off. These data show that subretinal implants can restore visual functions that are useful for daily life.

Decreased retinal sensitivity and loss of retinal nerve fibers in multiple system atrophy.

BACKGROUND AND AIM: In a previous study, retinal nerve fiber layer thickness (RNFLT) loss was shown as part of the neurodegenerative process in multiple system atrophy (MSA). Here, we investigate in a larger cohort of MSA patients whether the RNFLT loss translates into respective visual field defects. METHODS: Spectral domain optical coherence tomography was performed in 20 MSA patients (parkinsonian subtype = 12, cerebellar subtype = 8) to quantify peripapillary RNFLT. Visual field (90°) was analyzed by automated static perimetry to investigate retinal structure/function relationship. Eight data sets did not meet stringent quality criteria, and only 12 data sets were further analyzed. RESULTS: Compared to healthy controls, MSA patients demonstrated a significant reduction of RNFLT in the nasal sectors (p ( nasal-superior ) = 0.02, p ( nasal ) = 0.03, p ( nasal-inferior ) < 0.01), while changes in temporal RNFLT measures (p ( temporal-superior ) = 0.42, p ( temporal ) = 0.34, p ( temporal-inferior ) = 0.25) were not statistically significant compared to healthy controls (ANOVA). MSA patients featured a significant global mean deviation (2.74 dB; p < 0.01) without predominant peripheral visual field defects. Statistical analysis of mean defect in the central (0-30°), peripheral (30-90°) or global (0-90°) visual field revealed no significant correlation (r (2) (central) = 0.11, r (2) (peripheral) = 0.04, r (2) (global) = 0.07) with nasal RNFLT in MSA patients. CONCLUSION: MSA patients feature significant reduction in nasal RNFLT and global mean deviation when compared to healthy controls, consistent with the multi-systemic nature of this neurodegenerative disorder. This finding provides first evidence for two independent deteriorations of the visual system in MSA.

Optical coherence tomography shows progressive local nerve fiber loss after disc hemorrhages in glaucoma patients.

BACKGROUND AND AIM: The aim of this work is to investigate whether optic disc hemorrhages (ODH) lead to significant loss of nerve fibers at the lesion site over time and whether such a loss is reflected by visual field defects corresponding to the affected nerve fiber bundle. METHODS: In this retrospective study of ten sequential glaucoma patients (ten eyes) with ODH, we used high-resolution OCT circular scans (Spectralis HRA + OCT, Heidelberg Engineering, Heidelberg, Germany) to determine peripapillary retinal nerve fiber layer (RNFL) thickness at the time of ODH presentation and at follow-up visit between 3 and 6 months. Corresponding perimetric data were analyzed for global (mean defect, MD) and localized progression of visual field defects. RESULTS: ODH were mostly located in the inferior quadrant as determined clinically and from fundus photographs. Iterative OCT imaging revealed a significant RNFL reduction in the affected quadrant relative to the respective quadrant in the fellow eye (RNFL change = -2.25 ± 2.69 µm vs. 0.75 ± 2.78 µm, p = 0.01) within 120 ± 43 days. However, only three cases presented with new/progressive nerve fiber bundle defects corresponding to the lesion site within the given follow-up period. CONCLUSIONS: ODH lead to a significantly higher RNFL loss at the lesion site relative to the overall structural progression in glaucoma patients. However, this focal change is not generally reflected by respective nerve fiber bundle defects in the time frame investigated.

Biallelic Loss-of-Function NDUFA12 Variants Cause a Wide Phenotypic Spectrum from Leigh/Leigh-Like Syndrome to Isolated Optic Atrophy.

BACKGROUND: Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only. OBJECTIVES: To fully characterize, both phenotypically and genotypically, NDUFA12-related mitochondrial disease. METHODS: We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature. RESULTS: Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities (n = 6), optic atrophy (n = 2), or was unremarkable (n = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel. CONCLUSIONS: Our case series expands phenotype-genotype correlations in NDUFA12-associated mitochondrial disease, providing evidence of intra- and inter-familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh-like syndromes - particularly with dystonia - as well as isolated optic atrophy.

CT Assessment of Intraorbital Cable Movement of Electronic Subretinal Prosthesis in Three Different Surgical Approaches.

Purpose: Electronic retinal implants restore some visual perception in patients blind from retinitis pigmentosa. Eye movements cause mechanical stress in intraorbital power supply cables leading to cable breaks. By using computer tomography (CT) scans at the extreme positions of the four cardinal gaze directions, this study determined in vivo, which of three surgical routing techniques results in minimal bending radius variation and favors durability. Methods: Nine patients received the first-generation subretinal implant Alpha IMS (Retina Implant AG, Reutlingen, Germany) in one eye. Three techniques for intraorbital cable routing were used (straight cable route (A), parabulbar loop (B), and encircling band (C)), each in three patients. All patients underwent computer tomography of the orbital region. The bending radius of the intraorbital cable was measured with the DICOM viewer Osirix v4.1.2 (Pixmeo SARL, Bernex, Switzerland) and served as indicator for mechanical stress. Results: Average bending radius variation was 87% for method A, 11% for method B, and 16% for method C. Methods A and B (P = 0.005) and methods A and C (P = 0.007) differed significantly, while method B and C showed no statistical difference (P = 0.07). Conclusions: Compared to straight routes, arcuated cable routes significantly reduce cable movement and bending. Due to an easier surgical procedure, a parabulbar loop is the preferred method to minimize bending radius variation and prolong survival time of electronic subretinal implants. Translational Relevance: CT analysis of cable bending of implanted medical devices allows to determine which surgical routing technique favors durability in vivo.

FIG4 mutations leading to parkinsonism and a phenotypical continuum between CMT4J and Yunis Varón syndrome.

BACKGROUND: Charcot-Marie-Tooth disease type 4J (CMT4J) originates from mutations in the FIG4 gene and leads to distal muscle weakness. Two null alleles of FIG4 cause Yunis Varón syndrome with severe central nervous system involvement, cleidocranial dysmorphism, absent thumbs and halluces and early death. OBJECTIVES: To analyse the phenotypic spectrum of FIG4-related disease and explore effects of residual FIG4 protein. METHODS: Phenotyping of five new patients with FIG4-related disease. Western Blot analyses of FIG4 from patient fibroblasts. RESULTS: Next generation sequencing revealed compound heterozygous variants in FIG4 in five patients. All five patients presented with peripheral neuropathy, various degree of dysmorphism and a central nervous system involvement comprising Parkinsonism in 3/5 patients, cerebellar ataxia (1/5), spasticity of lower limbs (1/5), epilepsy (1/5) and/or cognitive deficits (2/5). Onset varied between the first and the seventh decade. There was no residual FIG4 protein detectable in fibroblasts of the four analysed patients. CONCLUSION: This study extends the phenotypic spectrum of FIG4-related disease to Parkinsonism as a feature and demonstrates new phenotypes on a continuum between CMT4J and Yunis Varón syndrome.

Confirmation of TACO1 as a Leigh Syndrome Disease Gene in Two Additional Families.

BACKGROUND: In 2009, we identified TACO1 as a novel mitochondrial disease gene in a single family, however no second family has been described to confirm the role of TACO1 in mitochondrial disease. OBJECTIVE: In this report, we describe two independent consanguineous families carrying pathogenic variants in TACO1, confirming the phenotype. METHODS: Detailed clinical investigations and whole exome sequencing with haplotype analysis have been performed in several members of the two reported families. RESULTS: Clinical phenotype of the patients confirms the originally reported phenotype of a childhood-onset progressive cerebellar and pyramidal syndrome with optic atrophy and learning difficulties. Brain MRI showed periventricular white matter lesions with multiple cystic defects, suggesting leukoencephalopathy in both patients. One patient carried the previously described homozygous TACO1 variant (p.His158ProfsTer8) and haplotype analysis suggested that this variant is a rare founder mutation. The second patient from another family carried a homozygous novel frame shift variant (p.Cys85PhefsTer15). CONCLUSIONS: The identification of two Turkish families with similar characteristic clinical presentation and an additional homozygous nonsense mutation confirms that TACO1 is a human mitochondrial disease gene. Although most patients with this clinical presentation undergo next generation sequencing analysis, screening for selected founder mutations in the Turkish population based on the precise clinical presentation may reduce time and cost of finding the genetic diagnosis even in the era of massively parallel sequencing.

Bi-allelic variants in RNF170 are associated with hereditary spastic paraplegia.

Alterations of Ca2+ homeostasis have been implicated in a wide range of neurodegenerative diseases. Ca2+ efflux from the endoplasmic reticulum into the cytoplasm is controlled by binding of inositol 1,4,5-trisphosphate to its receptor. Activated inositol 1,4,5-trisphosphate receptors are then rapidly degraded by the endoplasmic reticulum-associated degradation pathway. Mutations in genes encoding the neuronal isoform of the inositol 1,4,5-trisphosphate receptor (ITPR1) and genes involved in inositol 1,4,5-trisphosphate receptor degradation (ERLIN1, ERLIN2) are known to cause hereditary spastic paraplegia (HSP) and cerebellar ataxia. We provide evidence that mutations in the ubiquitin E3 ligase gene RNF170, which targets inositol 1,4,5-trisphosphate receptors for degradation, are the likely cause of autosomal recessive HSP in four unrelated families and functionally evaluate the consequences of mutations in patient fibroblasts, mutant SH-SY5Y cells and by gene knockdown in zebrafish. Our findings highlight inositol 1,4,5-trisphosphate signaling as a candidate key pathway for hereditary spastic paraplegias and cerebellar ataxias and thus prioritize this pathway for therapeutic interventions.