Genome sequencing reanalysis increases the diagnostic yield in dystonia.

PURPOSE: We investigated the contribution of genomic data reanalysis to the diagnostic yield of dystonia patients who remained undiagnosed after prior genome sequencing. METHODS: Probands with heterogeneous dystonia phenotypes who underwent initial genome sequencing (GS) analysis in 2019 were included in the reanalysis, which was performed through gene-specific discovery collaborations and systematic genomic data reanalysis. RESULTS: Initial GS analysis in 2019 (n = 111) identified a molecular diagnosis in 11.7 % (13/111) of cases. Reanalysis between 2020 and 2023 increased the diagnostic yield by 7.2 % (8/111); 3.6 % (4/111) through focused gene-specific clinical correlation collaborative efforts [VPS16 (two probands), AOPEP and POLG], and 3.6 % (4/111) by systematic reanalysis completed in 2023 [NUS1 (two probands) and DDX3X variants, and a microdeletion encompassing VPS16]. Seven of these patients had a high phenotype-based dystonia score ≥3. Notable unverified findings in four additional cases included suspicious variants of uncertain significance in FBXL4 and EIF2AK2, and potential phenotypic expansion associated with SLC2A1 and TREX1 variants. CONCLUSION: GS data reanalysis increased the diagnostic yield from 11.7 % to 18.9 %, with potential extension up to 22.5 %. While optimal timing for diagnostic reanalysis remains to be determined, this study demonstrates that periodic re-interrogation of dystonia GS datasets can provide additional genetic diagnoses, which may have significant implications for patients and their families.

Measurement of bradykinesia and chorea in Huntington's Disease using ambulatory monitoring.

Objectives: The feasibility of measuring bradykinesia and chorea in Huntington's Disease using a wearable sensor system (Parkinson's Kinetigraph: PKG) developed for measuring bradykinesia and dyskinesia in Parkinson's Disease was assessed. Methods: Unified Huntington's Disease Rating Scales (UHDRS) and a PKG were obtained for 25 people with Huntington's Disease. Bradykinesia and Chorea Score were derived from relevant sub-scores of the UHDRS and compared with the PKG's bradykinesia and dyskinesia scores. The PKG's daytime sleepiness score was also used. Results: There was good correlation between Chorea Scores and the PKG's dyskinesia score (Pearson's ρ = 0.66). Correlation between the Bradykinesia Scores and the PKG's bradykinesia score was also good (Pearson's ρ = 0.51) in cases whose PKG scores were in the normal or bradykinetic range. The PKG's bradykinesia score of 23, which is in the higher range of control subjects, separated participants into those with Independence Score ≥ 80 or < 80 and a Functional Assessment (FAS) score ≥ 18 or < 18. The PKG's daytime sleep score was high in 44 % of participants, whose average time asleep was 21 % compared to 1.6 % in participants with a normal sleep index. Participants with high sleep scores were significantly more likely to have low Independence and TFC scores. Conclusions: Measures of bradykinesia and dyskinesia from clinical scales have acceptable correlations with those from the PKG. Continuous monitoring provides information about daytime sleep, which was associated with lower functional status. Further studies and larger sample sizes are required to confirm these findings and the utility of this measure in Huntington's Disease.

Frequency and Characterization of Movement Disorders in Anti-IgLON5 Disease.

OBJECTIVE: Anti-IgLON5 disease is a recently described neurological disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are under-reported. Here we describe the frequency and types of movement disorders in a series of consecutive patients with this disease. METHODS: In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by three experts in movement disorders. RESULTS: Seventy two patients were included. In 41 (57%) the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least one movement disorder with a median of three per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients, 72%), chorea (24, 33%), bradykinesia (20, 28%), dystonia (19, 26%), abnormal body postures or rigidity (18, 25%), and tremor (15, 21%). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients, 32%) including dystonia (13), myorhythmia (6), chorea (4) or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31(43%) of patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only seven (13%) cases. CONCLUSIONS: Movement disorders are a frequent and leading cause of initial neurological consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

A blinded, controlled trial of objective measurement in Parkinson's disease.

Medical conditions with effective therapies are usually managed with objective measurement and therapeutic targets. Parkinson's disease has effective therapies, but continuous objective measurement has only recently become available. This blinded, controlled study examined whether management of Parkinson's disease was improved when clinical assessment and therapeutic decisions were aided by objective measurement. The primary endpoint was improvement in the Movement Disorder Society-United Parkinson's Disease Rating Scale's (MDS-UPDRS) Total Score. In one arm, objective measurement assisted doctors to alter therapy over successive visits until objective measurement scores were in target. Patients in the other arm were conventionally assessed and therapies were changed until judged optimal. There were 75 subjects in the objective measurement arm and 79 in the arm with conventional assessment and treatment. There were statistically significant improvements in the moderate clinically meaningful range in the MDS-UPDRS Total, III, IV scales in the arm using objective measurement, but not in the conventionally treated arm. These findings show that global motor and non-motor disability is improved when management of Parkinson's disease is assisted by objective measurement.

Whole genome sequencing for the genetic diagnosis of heterogenous dystonia phenotypes.

INTRODUCTION: Dystonia is a clinically and genetically heterogeneous disorder and a genetic cause is often difficult to elucidate. This is the first study to use whole genome sequencing (WGS) to investigate dystonia in a large sample of affected individuals. METHODS: WGS was performed on 111 probands with heterogenous dystonia phenotypes. We performed analysis for coding and non-coding variants, copy number variants (CNVs), and structural variants (SVs). We assessed for an association between dystonia and 10 known dystonia risk variants. RESULTS: A genetic diagnosis was obtained for 11.7% (13/111) of individuals. We found that a genetic diagnosis was more likely in those with an earlier age at onset, younger age at testing, and a combined dystonia phenotype. We identified pathogenic/likely-pathogenic variants in ADCY5 (n = 1), ATM (n = 1), GNAL (n = 2), GLB1 (n = 1), KMT2B (n = 2), PRKN (n = 2), PRRT2 (n = 1), SGCE (n = 2), and THAP1 (n = 1). CNVs were detected in 3 individuals. We found an association between the known risk variant ARSG rs11655081 and dystonia (p = 0.003). CONCLUSION: A genetic diagnosis was found in 11.7% of individuals with dystonia. The diagnostic yield was higher in those with an earlier age of onset, younger age at testing, and a combined dystonia phenotype. WGS may be particularly relevant for dystonia given that it allows for the detection of CNVs, which accounted for 23% of the genetically diagnosed cases.

Role of the Personal KinetiGraph in the routine clinical assessment of Parkinson's disease: recommendations from an expert panel.

INTRODUCTION: Evaluation of people with Parkinson's disease (PD) is often complex due to heterogeneity of symptoms and disease course, including the variability of motor fluctuations and dyskinesia. Routine clinical evaluations may be incomplete, may not accurately capture important symptoms, and may not reflect day-to-day variability. While significant advances have been made in wearable ambulatory continuous objective monitoring (COM) technologies, many clinicians remain uncertain of how to incorporate them in clinical practice, including the value to clinical decision-making. The Personal KinetiGraph™ (PKG) has FDA clearance in the United States, and has recently been used in several clinical studies. Areas covered: An expert group of movement disorders neurologists convened to discuss the clinical utility of the PKG in the routine assessment of people with PD. Based on their experience, the group identified clinical scenarios where objective information gained from review of PKG reports can provide useful information to improve clinical management. Expert commentary: PKG provides clinically meaningful data in patients with PD that can aid the clinician in evaluating patients and optimizing their pharmacologic therapy. Early clinical experience and expert opinion suggest that utilization of COM technologies such as the PKG have the potential to improve medical care in people with PD.

Treatable inherited rare movement disorders.

There are many rare movement disorders, and new ones are described every year. Because they are not well recognized, they often go undiagnosed for long periods of time. However, early diagnosis is becoming increasingly important. Rapid advances in our understanding of the biological mechanisms responsible for many rare disorders have enabled the development of specific treatments for some of them. Well-known historical examples include Wilson disease and dopa-responsive dystonia, for which specific and highly effective treatments have life-altering effects. In recent years, similarly specific and effective treatments have been developed for more than 30 rare inherited movement disorders. These treatments include specific medications, dietary changes, avoidance or management of certain triggers, enzyme replacement therapy, and others. This list of treatable rare movement disorders is likely to grow during the next few years because a number of additional promising treatments are actively being developed or evaluated in clinical trials. © 2017 International Parkinson and Movement Disorder Society.

Clinical manifestations of the anti-IgLON5 disease.

OBJECTIVE: To report the presentation, main syndromes, human leukocyte antigen (HLA) association, and immunoglobulin G (IgG) subclass in the anti-IgLON5 disease: a disorder with parasomnias, sleep apnea, and IgLON5 antibodies. METHODS: This was a retrospective clinical analysis of 22 patients. The IgG subclass was determined using reported techniques. RESULTS: Patients' median age was 64 years (range 46-83). Symptoms that led to initial consultation included sleep problems (8 patients; 36%), gait abnormalities (8; 36%), bulbar dysfunction (3; 14%), chorea (2; 9%), and cognitive decline (1; 5%). By the time of diagnosis of the disorder, 4 syndromes were identified: (1) a sleep disorder with parasomnia and sleep breathing difficulty in 8 (36%) patients; (2) a bulbar syndrome including dysphagia, sialorrhea, stridor, or acute respiratory insufficiency in 6 (27%); (3) a syndrome resembling progressive supranuclear palsy (PSP-like) in 5 (23%); and (4) cognitive decline with or without chorea in 3 (14%). All patients eventually developed parasomnia, sleep apnea, insomnia, or excessive daytime sleepiness. HLA-DRB1*10:01 and HLA-DQB1*05:01 were positive in 13/15 (87%) patients; the DRB1*10:01 allele was 36 times more prevalent than in the general population. Among 16 patients with paired serum and CSF samples, 14 had IgLON5 antibodies in both, and 2 only in serum (both had a PSP-like syndrome). Twenty of 21 patients had IgG1 and IgG4 antibodies; the latter predominated in 16. CONCLUSIONS: Patients with IgLON5 antibodies develop a characteristic sleep disorder preceded or accompanied by bulbar symptoms, gait abnormalities, oculomotor problems, and, less frequently, cognitive decline. IgG4 subclass antibodies predominate over IgG1; we confirm a strong association with the HLA-DRB1*10:01 allele.

A conditioned response as a measure of impulsive-compulsive behaviours in Parkinson's disease.

OBJECTIVES: Parkinson's Disease patients wore a device on the wrist that gave reminders to take levodopa and also measured bradykinesia and dyskinesia. Consumption of medications was acknowledged by placing the thumb on the device. Some patients performed this acknowledgement repeatedly and unconsciously. This study examines whether this behaviour reflected increased impulsivity. METHODS AND RESULTS: Twenty five participants were selected because they had i) excess acknowledgements described above or ii) Impulsive-Compulsive Behaviours or iii) neither of these. A blinded assessor applied clinical scales to measure Impulsive-Compulsive Behaviours, cognition, depression, anxiety and apathy. A Response Ratio, representing the number of acknowledgements/number of doses (expressed as a percentage) was tightly correlated with ratings of Impulsive-Compulsive Behaviours (r²â€Š= 0.79) in 19/25 subjects. Some of these patients had dyskinesia, which was higher with extraneous responses than with response indicating medication consumption. Six of the 25 subjects had high Impulsive-Compulsive Behaviour Scores, higher apathy scores, low levels of dyskinesia and normal Response Ratios. Patients without ICB (low RR) also had low dyskinesia levels regardless of the relevance of the response. CONCLUSION: An elevated Response Ratio is a specific measure of a type of ICB where increased incentive salience is attributed to cues by the presence of high striatal dopamine levels, manifested by high levels of dyskinesia. This study also points to a second form of ICBs which occur in the absence of dyskinesia, has normal Response Ratios and higher apathy scores, and may represent prefrontal pathology.

FOSMN syndrome: novel insight into disease pathophysiology.

OBJECTIVE: To better define the pathophysiologic mechanisms underlying the development of the novel facial-onset sensory and motor neuronopathy (FOSMN) syndrome and, in particular, to determine whether neurodegenerative processes, mediated by excitotoxicity, or autoimmune mechanisms contribute to the development of FOSMN syndrome. METHODS: Clinical, laboratory, neurophysiologic, and pathologic assessments were undertaken for 5 patients with FOSMN syndrome (3 male and 2 female), the largest cohort of FOSMN syndrome reported to date. In addition to conventional neurophysiologic studies, novel threshold tracking transcranial magnetic stimulation (TMS) techniques were undertaken to assess for the presence of cortical excitability. RESULTS: Clinically, all patients exhibited the typical FOSMN syndrome phenotype, heralded by facial-onset sensory deficits with subsequent development of motor deficits evolving in a rostral-caudal direction. Pathologic studies, including an autopsy, disclosed widespread degeneration of sensory and motor neurons with no evidence of inflammation, amyloid deposition, or intraneuronal inclusions, such as TDP-43, Bunina bodies, or ubiquitin inclusions. Conventional neurophysiologic studies revealed abnormalities of blink reflexes, along with features of motor and sensory neuronopathy. Threshold tracking TMS disclosed normal cortical excitability in patients with FOSMN syndrome, with preserved short-interval intracortical inhibition, resting motor threshold, motor evoked potential amplitude, and cortical silent period duration. Patients with FOSMN syndrome failed to respond to immunomodulatory approaches. CONCLUSIONS: Findings from the present study suggest that FOSMN syndrome is a primary neurodegenerative disorder of sensory and motor neurons, with distinct pathophysiologic mechanisms.

Dysexecutive behaviour following deep brain lesions--a different type of disconnection syndrome?

The suppression of automatic prepotent behaviour in favour of more successful, more 'appropriate' behaviour is the primary function of the frontal lobe. Five frontal-subcortical circuits connect the frontal lobe to the basal ganglia and the thalamus. We report 17 patients with small lesions in the downstream structures of the frontal-subcortical circuits displaying severe dysexecutive behaviour. Positron emission tomography (PET) demonstrated hypometabolism of the frontal lobe in some of these patients. The literature on frontal lobe dysfunction after lesions in the basal ganglia and thalamus is discussed and the semiology of frontal lobe dysfunction in relation to the frontal-subcortical circuits is highlighted. Derived from our findings we suggest a disconnection syndrome of the frontal lobe caused by lesions in the downstream structures of the frontal-subcortical circuits.

Automated assessment of bradykinesia and dyskinesia in Parkinson's disease.

There is a need for objective measures of dyskinesia and bradykinesia of Parkinson's disease (PD) that are continuous throughout the day and related to levodopa dosing. The output of an algorithm that calculates dyskinesia and bradykinesia scores every two minutes over 10 days (PKG: Global Kinetics Corporation) was compared with conventional rating scales for PD in PD subjects. The algorithm recognises bradykinesia as movements made with lower acceleration and amplitude and with longer intervals between movement. Similarly the algorithm recognises dyskinesia as having movements of normal amplitude and acceleration but with shorter periods without movement. The distribution of the bradykinesia and dyskinesia scores from PD subjects differed from that of normal subjects. The algorithm predicted the clinical dyskinesia rating scale AIMS with a 95% margin of error of 3.2 units compared with the inter-rater 95% limits of agreement from 3 neurologists of -3.4 to +4.3 units. Similarly the algorithm predicted the UPDRS III score with a margin of error similar to the inter-rater limits of agreement. Improvement in scores in response to changes in medication could be assessed statistically in individual patients. This algorithm provides objective, continuous and automated assessment of the clinical features of bradykinesia and dyskinesia in PD.

Novel pathogenic mutations and copy number variations in the VPS13A gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is a rare autosomal recessive neurodegenerative disorder caused by loss of function mutations in the vacuolar protein sorting 13 homolog A (VPS13A) gene that encodes chorein. It is characterized by adult-onset chorea, peripheral acanthocytes, and neuropsychiatric symptoms. In the present study, we performed a comprehensive mutation screen, including sequencing and copy number variation (CNV) analysis, of the VPS13A gene in ChAc patients. All 73 exons and flanking regions of VPS13A were sequenced in 35 patients diagnosed with ChAc. To detect CNVs, we also performed real-time quantitative PCR and long-range PCR analyses for the VPS13A gene on patients in whom only a single heterozygous mutation was detected. We identified 36 pathogenic mutations, 20 of which were previously unreported, including two novel CNVs. In addition, we investigated the expression of chorein in 16 patients by Western blotting of erythrocyte ghosts. This demonstrated the complete absence of chorein in patients with pathogenic mutations. This comprehensive screen provides an accurate and useful method for the molecular diagnosis of ChAc.

Shape alterations in the striatum in chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is an uncommon autosomal recessive disorder due to mutations of the VPS13A gene, which encodes for the membrane protein chorein. ChAc presents with progressive limb and orobuccal chorea, but there is often a marked dysexecutive syndrome. ChAc may first present with neuropsychiatric disturbance such as obsessive-compulsive disorder (OCD), suggesting a particular role for disruption to striatal structures involved in non-motor frontostriatal loops, such as the head of the caudate nucleus. Two previous studies have suggested a marked reduction in volume in the caudate nucleus and putamen, but did not examine morphometric change. We investigated morphometric change in 13 patients with genetically or biochemically confirmed ChAc and 26 age- and gender-matched controls. Subjects underwent magnetic resonance imaging and manual segmentation of the caudate nucleus and putamen, and shape analysis using a non-parametric spherical harmonic technique. Both structures showed significant and marked reductions in volume compared with controls, with reduction greatest in the caudate nucleus. Both structures showed significant shape differences, particularly in the head of the caudate nucleus. No significant correlation was shown between duration of illness and striatal volume or shape, suggesting that much structural change may have already taken place at the time of symptom onset. Our results suggest that striatal neuron loss may occur early in the disease process, and follows a dorsal-ventral gradient that may correlate with early neuropsychiatric and cognitive presentations of the disease.

Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism.

PURPOSE: Our previous results showed that both gray zone and lower end premutation range (40-85 repeats) fragile X mental retardation 1 (FMR1) alleles were more common among males with parkinsonism than in the general population. This study aimed to determine whether these alleles have a significant role in the manifestations and pathogenesis of parkinsonian disorders. METHODS: Detailed clinical assessment and genetic testing were performed in 14 male carriers of premutation and gray zone FMR1 alleles and in 24 noncarriers identified in a sample of males with parkinsonism. RESULTS: The premutation + gray zone carriers presented with more severe symptoms than disease controls matched for age, diagnosis, disease duration, and treatment. The Parkinson disease (Unified Parkinson's Disease Rating Scale) motor score and the measures of cognitive decline (Mini-Mental State Examination and/or Addenbrooke's Cognitive Examination Final Revised Version A scores) were significantly correlated with the size of the CGG repeat and the (elevated) levels of antisense FMR1 and Cytochrome C1 mRNAs in blood leukocytes. In addition, the carriers showed a significant depletion of the nicotinamide adenine dinucleotide, reduced dehydrogenase subunit 1 mitochondrial gene in whole blood. CONCLUSION: Small CGG expansion FMR1 alleles (gray zone and lower end premutation) play a significant role in the development of the parkinsonian phenotype, possibly through the cytotoxic effect of elevated sense and/or antisense FMR1 transcripts involving mitochondrial dysfunction and leading to progressive neurodegeneration.

Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease.

Data regarding the effect of deep brain stimulation (DBS) surgery on the dopamine dysregulation syndrome (DDS), impulse control disorders (ICDs) and punding in Parkinson's disease (PD) are limited. We present a case series of 21 operated PD patients who had exhibited DDS, ICDs or punding at some stage during the disease. DDS remained unimproved or worsened post-operatively in 12/17 patients with pre-operative DDS (71%) (nine bilateral subthalamic nucleus [STN], one right-sided STN, two bilateral globus pallidus internus [GPi] DBS). DDS improved or resolved after bilateral STN DBS in 5/17 patients with pre-operative DDS. DDS apparently developed for the first time after bilateral STN DBS in two patients, although only after a latency of eight years in one case. One patient without reported pre-operative DDS or ICDs developed pathological gambling post-STN DBS. One patient had pathological gambling which resolved pre-operatively, and did not recur post-DBS. Thus, DDS, ICDs and punding may persist, worsen or develop for the first time after DBS surgery, although a minority of patients improved dramatically. Predictive factors may include physician vigilance, motor outcome and patient compliance.

C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy.

Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease activity but lose normal perinuclear localization. These data have implications for the maintenance of vascular integrity in the degenerative cerebral microangiopathies leading to stroke and dementias.

Prevalence and clinical features of common LRRK2 mutations in Australians with Parkinson's disease.

We determined the prevalence of two common leucine-rich repeat kinase 2 (LRRK2) gene mutations in Australian patients with Parkinson's disease (PD). Of 830 affected patients, eight were heterozygous for the G2019S mutation, and two were heterozygous for the R1441H (4,322 G > A) mutation. In addition, one familial patient had a novel A1442P (4,324 G > C) mutation. Haplotype analysis showed that all LRRK2 G2019S-positive individuals carried the common founder haplotype 1 and a putative founder haplotype for the R1441H mutation carriers. Clinically, patients with LRRK2 mutations had typical levodopa responsive Parkinsonism with tremor being the commonest presenting feature. Patients with the G2019S mutation in our series had a similar age of onset of symptoms when compared with patients with other LRRK2 mutations or sporadic PD, although they were more likely to have a family history of PD (2.4% of Australian patients with familial PD and 0.3% of Australian patients with sporadic PD). Our results demonstrate that the G2019S mutation carriers share the same ancestors who migrated to Australia originally from Europe and that other LRRK2 mutations (R1441H and A1442P) can be found in this population.

Novel ophthalmological features in hereditary endotheliopathy with retinopathy, nephropathy and stroke syndrome.

The ophthalmic features are reported of a member of an Australian pedigree with three affected individuals spanning two generations with a hereditary endotheliopathy syndrome resulting in retinopathy, leukoencephalopathy and nephropathy. The index case initially presented with asymptomatic retinopathy, cerebral microvascular disease, nephropathy and raised inflammatory markers. The clinical, neuro-radiological, biochemical and histopathological findings in this patient are consistent with a diagnosis of hereditary endotheliopathy, retinopathy, nephropathy and stroke (HERNS). Linkage analysis has identified a locus for HERNS on chromosome 3p21.1-p21.3. This locus is shared with two other diseases: hereditary vascular retinopathy (HVR) and cerebroretinal vasculopathy (CRV). Although peripheral retinal involvement is a feature of HVR, it has not previously been described in HERNS. This case represents a novel phenotype of HERNS, and serves to blur the distinction between the vasculopathies mapping to chromosome 3p21. Although previously thought to be distinct clinical entities, it is possible that HERNS, HVR and CRV simply represent different phenotypes of the same disease. This will only be clarified with the identification of the gene or genes. This case also raises the question of how best to manage rare forms of vascular retinopathy.