Cardiac phenotype in ATP1A3-related syndromes: A multicenter cohort study.

OBJECTIVE: To define the risks and consequences of cardiac abnormalities in ATP1A3-related syndromes. METHODS: Patients meeting clinical diagnostic criteria for rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS) with ATP1A3 genetic analysis and at least 1 cardiac assessment were included. We evaluated the cardiac phenotype in an Atp1a3 knock-in mouse (Mashl+/-) to determine the sequence of events in seizure-related cardiac death. RESULTS: Ninety-eight patients with AHC, 9 with RDP, and 3 with CAPOS (63 female, mean age 17 years) were included. Resting ECG abnormalities were found in 52 of 87 (60%) with AHC, 2 of 3 (67%) with CAPOS, and 6 of 9 (67%) with RDP. Serial ECGs showed dynamic changes in 10 of 18 patients with AHC. The first Holter ECG was abnormal in 24 of 65 (37%) cases with AHC and RDP with either repolarization or conduction abnormalities. Echocardiography was normal. Cardiac intervention was required in 3 of 98 (≈3%) patients with AHC. In the mouse model, resting ECGs showed intracardiac conduction delay; during induced seizures, heart block or complete sinus arrest led to death. CONCLUSIONS: We found increased prevalence of ECG dynamic abnormalities in all ATP1A3-related syndromes, with a risk of life-threatening cardiac rhythm abnormalities equivalent to that in established cardiac channelopathies (≈3%). Sudden cardiac death due to conduction abnormality emerged as a seizure-related outcome in murine Atp1a3-related disease. ATP1A3-related syndromes are cardiac diseases and neurologic diseases. We provide guidance to identify patients potentially at higher risk of sudden cardiac death who may benefit from insertion of a pacemaker or implantable cardioverter-defibrillator.

Wilson disease-treatment perspectives.

Wilson disease (WD) is a genetic disorder caused by pathological tissue copper accumulation with secondary damage of affected organs (mainly, but not limited to, the liver and brain). The main clinical symptoms of WD are, in concordance with the pathogenesis, hepatic and/or neuropsychiatric. Current treatment options for WD, based on drugs leading to negative copper body balance like chelators or zinc salts, were introduced more than 40 years ago and are generally effective in the majority of WD cases if used lifelong. However, especially in neurological patients, treatment may lead to neurological deterioration, which is often irreversible. Further, almost 50% of neurologically affected WD patients present with persistent neurological deficits despite the use of anti-copper treatment. In addition, up to 30% of patients treated with the widely used drug, d-penicillamine, present with adverse events related to treatment, which often leads to treatment discontinuation. Finally, almost 25% of WD patients do not adhere with anti-copper treatment, partially due to drug-related adverse events and complex treatment regimens (3 times daily, before meals, etc.). These limitations with current treatments have led to the search for other WD treatment possibilities. Currently, research is mainly focused on: (I) new agents with better safety profiles and less neurological deterioration properties compared with traditional chelators, e.g., tetrathiomolybdate salts or central nervous system-penetrable trientine, with the aim to provide more effective copper removal from brain tissue; (II) other non-chelating drugs that lead to removal of copper from cells [e.g., methanobactin (currently in preclinical studies)]; (III) cell and gene therapy. In this article, current research on future treatments for WD is reviewed.

Brain volume is related to neurological impairment and to copper overload in Wilson's disease.

INTRODUCTION: To determine whether brain volume was associated with functional and neurological impairments and with copper overload markers in patients with Wilson's disease. METHODS: In 48 treatment-naïve patients, we assessed functional and neurological impairments with the Unified Wilson's Disease Rating Scale, measured normalized brain volumes based on magnetic resonance images, and assessed concentration of non-ceruloplasmin-bound copper. We correlated brain volume measures with functional and neurological impairment scores and copper overload indices. RESULTS: Functional and neurological impairments correlated with all brain volume measures, including the total brain volume and the volumes of white matter and gray matter (both peripheral gray matter and deep brain nuclei). Higher non-ceruloplasmin-bound copper concentrations were associated with greater functional and neurological impairments and lower brain volumes. CONCLUSIONS: Our findings provided the first in vivo evidence that the severity of brain atrophy is a correlate of functional and neurological impairments in patients with Wilson's disease and that brain volume could serve as a marker of neurodegeneration induced by copper.

Anterior segment optical coherence tomography (AS-OCT) as a new method of detecting copper deposits forming the Kayser-Fleischer ring in patients with Wilson disease.

PURPOSE: Kayser-Fleischer ring pathognomonic for Wilson disease (WD) is formed of corneal copper deposits present predominantly within the anterior chamber angle at the Schwalbe's line. The slit-lamp assessment commonly used as a standard of care cannot detect them early enough, as the angle view is obscured by the corneal limbus. The aim of the research was to evaluate the anterior segment optical coherence tomography (AS-OCT), as objective diagnostic assessment of copper deposits forming KF ring in patients with WD. METHODS: Twenty-nine subjects (17 women) and twenty-nine controls (14 women) were enrolled and underwent slit lamp and AS-OCT assessment. RESULTS: Kayser-Fleischer ring was not detected - either with a slit lamp or with AS-OCT - in any of the controls. Fifteen subjects presenting without KF ring at a slit-lamp examination were found to have a KF ring when examined with AS-OCT (p < 0.001), which confirms improved accuracy of AS-OCT, as compared to the slit-lamp examination. CONCLUSION: Our results support AS-OCT as a diagnostic procedure to offer better objectivity and accuracy as compared to a slit-lamp examination, both at the diagnostic stage and when monitoring changes in KF ring during medical therapy to assess its efficacy and patient compliance.

Whole-exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype.

BACKGROUND & AIMS: Wilson's disease (WD) is an autosomal recessive disorder associated with disease-causing alterations across the ATP7B gene, with highly variable symptoms and age of onset. We aimed to assess whether the clinical variability of WD relates to modifier genes. METHODS: A total of 248 WD patients were included, of whom 148 were diagnosed after age of 17. Human exome libraries were constructed using AmpliSeq technology and sequenced using the IonProton platform. RESULTS: ATP7B p.His1069Gln mutation was present in 215 patients, with 112 homozygotes and 103 heterozygotes. Three other mutations: p.Gln1351Ter, p.Trp779Ter and c.3402delC were identified in >10 patients. Among patients, 117 had a homozygous mutation, 101 were compound heterozygotes, 27 had one heterozygous mutation, and 3 other patients had no identifiable pathogenic variant of ATP7B. Sixteen mutations were novel, found as part of a compound mutation or as a sole, homozygous mutation. For disease phenotype prediction, age at diagnosis was a deciding factor, while frameshift allelic variants of ATP7B and being male increased the odds of developing a neurological phenotype. Rare allelic variants in ESD and INO80 increased and decreased chances for the neurological phenotype, respectively, while rare variants in APOE and MBD6 decreased the chances of WD early manifestation. Compound mutations contributed to earlier age of onset. CONCLUSIONS: In a Polish population, genetic screening for WD may help genotype for four variants (p.His1069Gln, p.Gln1351Ter, p.Trp779Ter and c.3402delC), with direct sequencing of all ATP7B amplicons as a second diagnostic step. We also identified some allelic variants that may modify a WD phenotype.

Alternating Hemiplegia of Childhood in Two Adult Patients with a Mild Syndrome.

We describe the cognitive-behavioral functioning of two adult patients with a mild form of alternating hemiplegia of childhood (AHC). AHC is a rare, chronic neurodevelopmental syndrome manifesting in infancy or early childhood, with recurrent hemiplegic or hemidystonic attacks, various nonepileptic paroxysmal events, and cognitive-behavioral impairments, including mental delay of varying degrees. We conducted neurologic and neuroimaging examinations, as well as a neuropsychological assessment, of two men (22 and 30 years old) with mutations in the ATP1A3 gene (p.Leu757Pro and p.Val332Glu) who were experiencing typical AHC transient episodes of alternating weakness or paralysis in order to investigate causes of their poor social functioning. During neurologic examinations of both patients, which were performed between attacks, we observed involuntary movements such as chorea and upper-limb tremor. One patient also had dysarthria. Magnetic resonance imaging revealed no parenchymal brain lesions or atrophy in either patient. Neuropsychological examinations demonstrated near-normal (patient 1) or normal (patient 2) global cognitive functioning, with some isolated executive functioning deficits. Both patients had emotional and social dysfunction as well as difficulties adapting to normal adult life. Although the clinical presentation of AHC is usually dramatic, some patients have mild forms of the syndrome (eg, no significant intellectual disability). However, motor and movement disorders, as well as coexisting emotional-affective abnormalities, may affect these patients' ability to adapt to independent life.

Psychiatric manifestations in Wilson's disease: possibilities and difficulties for treatment.

Wilson's disease (WD) is an inherited metabolic disorder related to disturbances of copper metabolism, and predominantly presents with liver and neuropsychiatric symptoms. In most cases it can be successfully treated with anti-copper agents, and both liver function and neuropsychiatric symptoms typically improve. Treatment guidelines for WD include recommendations for anti-copper treatment as well as for the treatment of liver failure symptoms. Recently, recommendations for treatment of the neurological symptoms of WD have also been proposed. Although most WD patients present with psychiatric symptoms at some stage of the disease, currently there are no guidelines for the treatment of the psychiatric manifestations. Treatment of the psychiatric symptoms of WD is often guided by general psychiatric experience, which typically glosses over the specificity of WD, and can result in severe neurological and/or hepatic complications. Here we review and discuss the possible treatments available for the mood disturbances, psychosis, behavioral and cognitive disorders that can occur in WD, as well as their efficacy.

Characteristics of a newly diagnosed Polish cohort of patients with neurological manifestations of Wilson disease evaluated with the Unified Wilson's Disease Rating Scale.

BACKGROUND: Wilson disease is a rare genetic disorder in which impaired copper excretion results in toxic copper levels and tissue damage. Manifestations are primarily hepatic and/or neuropsychiatric, with a variety of neurological phenotypes. The aim of this study was to characterize neurological signs of Wilson disease in newly diagnosed patients and to determine whether they correlated with disability, liver function, and copper metabolism. METHODS: Fifty-three treatment-naïve patients recently diagnosed with Wilson disease who exhibited neurological symptoms were included. Neurological manifestations were characterized by examination in terms of symptom type and degree of neurological impairment (Unified Wilson's Disease Rating Scale [UWDRS] Part III) and correlated with degree of disability (UWDRS Part II), abnormalities in copper parameters and hepatic status. RESULTS: Most patients (62.3%) exhibited tremor and ataxia, whereas 15.1% were dystonic, and 11.3% had parkinsonism. Discrete or unclassified signs only were observed in 11.3% of patients. A good correlation between disability (UWDRS Part II) and neurological impairment (UWDRS Part III) was observed (Pearson r = 0.84). However, there was a lack of correlation when either disability or neurological impairment were analyzed with copper parameters or liver impairment. CONCLUSIONS: The predominant neurological manifestations in this cohort of newly diagnosed Wilson disease patients were ataxia and tremor. Neurological impairment measured was highly correlated with the level of disability. However, hepatic manifestations of Wilson disease and copper levels did not appear to be correlated with neurological status and disability. These results highlight the challenges faced when assessing Wilson disease with its highly variable symptomatology.

Optical coherence tomography as a marker of neurodegeneration in patients with Wilson's disease.

Wilson's disease (WD) is an inherited autosomal recessive disorder that leads to pathological copper accumulation in different organs. Optical coherence tomography (OCT) is proposed as a marker of neurodegeneration in many neurological diseases. Thinning of the total retinal nerve fiber layer (RNFL) and macular thickness (Mth) examined by OCT was detected in patients with WD, especially those with brain magnetic resonance imaging changes. The aim of this study was to evaluate the relationship between OCT parameters and the progression of neurological signs measured by the Unified Wilson's Disease Rating Scale (UWDRS) in patients with WD. Consecutive patients with WD admitted to the Department of Neurology underwent OCT to assess the thickness of the macula and total RNFL. Patients also had neurologic assessments according to the UWDRS part III. Patients were divided into two groups based on the presence (UWDRS+) and absence (UWDRS-) of neurological symptoms. Fifty-eight patients (34 females, 24 males) were enrolled. Mean duration of treatment was 9 years (standard deviation [SD], ±10.8). The mean UWDRS score at the time of study was 8.4 (range 1-52; SD ±13.9) points. Total RNFL as well as macula thickness were significantly decreased in the UWDRS+ group versus the UWDRS- group. A significant negative correlation was found between OCT parameters (RNFL and Mth measurements) and neurological impairment according the UWDRS scale. This study confirms that OCT may be a useful tool for measuring the degree of neurodegeneration in patients with WD, and may play role in monitoring disease progression.

Other organ involvement and clinical aspects of Wilson disease.

Wilson disease (WD) is a rare disorder of copper metabolism that presents mainly with hepatic and neuropsychiatric features. Copper accumulates not only in the liver and brain, but also in other organs. Liver injury can also be the cause of secondary impairment of other tissues. Therefore, the clinical manifestation of WD may be renal, cardiac, skin, osteoarticular, or endocrinologic and include other organ disturbances. Renal abnormalities include tubular dysfunction (e.g., renal tubular acidosis, aminoaciduria) and nephrolithiasis. Bone demineralization is a common manifestation in patients with WD. Cardiac injury may include arrhythmia, cardiomyopathy, and autonomic dysfunction. Different endocrine system manifestations, such as infertility or repeated miscarriages, growth and puberty disturbances, and hypoparathyroidism, are observed. Other important clinical aspects of WD include pancreas involvement, immunologic abnormalities, the presence of lipomas, and skin changes. Although other organ involvement is not common in WD and usually not severe, delayed diagnosis may lead to irreversible changes in organs and tissues. Therefore, awareness of other possible WD presentations is important in the differential diagnosis of WD.

Psychiatric disturbances as a first clinical symptom of Wilson's disease - case report. / Zaburzenia psychiatryczne jako pierwszy objaw choroby Wilsona - opis przypadku.

OBJECTIVES: Wilson's disease (WD) is an inherited disorder of copper metabolism with wide spectrum of clinical symptoms, mainly hepatic or neurological. Psychiatric disorders occur less frequently and are not pathognomonic for WD. However, in almost 20% of cases they are in fact the first clinical manifestation of WD. The aim of this paper is to emphasise the importance of including WD in differential diagnosis of psychiatric disorders in young adults, as well as caution in initiating psychiatric treatment for patients with already established diagnosis of WD. METHODS: Case report of a patient with primarily psychiatric manifestation of WD. RESULTS: The authors present the case of a 26-year-old patient treated for 3 years due to depressive syndrome who was diagnosed as WD in the differential diagnosis shortly after extrapyramidal symptoms developed. During the further WD treatment the manic episode occurred. The patient was treated with atypical neuroleptics and anxiolytics, with good psychiatric effect, but with severe neurological deterioration. However, long term use of valproic acid and olanzapine combined with continuation of anti-copper treatment and rehabilitation resulted in good psychiatric and neurological outcome. CONCLUSIONS: WD should be always considered in differential diagnosis of psychiatric disorders in young patients, especially if they present additional extrapyramidal or hepatic symptoms. It is also extremely important to remain cautious when drugs with high affinity to dopamine D2 receptors need to be initiated in patients already diagnosed with WD, as they may result in severe and often irreversible neurological complications.

The sunflower cataract in Wilson's disease: pathognomonic sign or rare finding?

The presence of Kayser-Fleischer ring in patients with Wilson's disease (WD) is well documented and included in diagnostic algorithms; however, data about the occurrence of the second postulated ophthalmological sign of WD, sunflower cataract (SC), are limited and even conflicting. The aim of our study was to verify the occurrence of SC in WD. From January 2010 to May 2015, 81 consecutive, newly diagnosed WD patients underwent detailed ophthalmological examinations, including slit lamp examination with special attention to lens transparency, to verify the presence of SC in WD-naive patients. SC was detected in only one (1.2 %) of the examined WD patients, did not impact visual acuity; moreover, completely disappeared following a year of treatment for WD. SC may be a very rare and reversible ophthalmological manifestation of WD that is observed seldom and only at the time of WD diagnosis. We postulate that a finding of SC in WD patients is an interesting finding that may occur in the course of WD, but it is not a pathognomonic sign of WD.

Frequencies of initial gait disturbances and falls in 100 Wilson's disease patients.

Wilson's disease (WD) is an inherited copper metabolism disorder. Gait disturbances may present with both extrapyramidal and cerebellar patterns. The frequencies of particular types of gait abnormalities have not been established; thus, the aim of the present study was to determine the occurrence of initial gait disturbances among our neurological WD patients. We analyzed 103 WD patients with neurological features at the time of diagnosis, between 2005 and 2014. The neurological and gait assessments were based on the Unified Wilson's Disease Score Scale (UWDRS), from which, we distinguished three main patterns of gait: dystonic, ataxic, or Parkinsonian. All types of gait impairment were assessed using four stages of severity (0=normal, 4=severe). We also obtained each patient's history of falls. Three patients had severe dystonia of limbs and were unable to stand or walk. Gait abnormalities were noted in 59% (59/100) of the remaining group of patients. The most common observed pattern was ataxic gait (45%; 27/59), which presented as impaired tandem in most cases. A mixed gait impairment was observed in 25% (15/59) of patients (ataxic, dystonic, and Parkinsonian, n=8; ataxic and Parkinsonian, n=7), a Parkinsonian gait in 18% (11/59), and a dystonic gait in 10% (6/59) of patients. Falls were noted in 35% of patients, but were occasionally observed in most cases. Gait disturbances are frequent in WD, and reflect the involvement of many brain structures.

Early neurological worsening in patients with Wilson's disease.

BACKGROUND: Early neurological worsening during treatment initiation for Wilson's disease (WD) is an unresolved problem. Our aim was to establish the frequency and outcome of early neurological worsening in patients with WD. METHODS: We analyzed 143 symptomatic patients diagnosed with WD between 2005 and 2009. Early neurological deterioration was based on worsening on the Unified Wilson's Disease Score Scale, scored at baseline through 6 months or occurrence of new neurological symptoms. Reversibility of worsening was followed up to 24 months. RESULTS: Early neurological worsening was observed in 11.1% (16/143) and involved only patients with neurological signs at diagnosis. Mean time to worsening from treatment initiation was 2.3 ± 1.9 months. Neurological deterioration was completely reversible in 53% (8/15) and partially in 13% (2/15) of patients over 9.2 ± 5.2 months. Patients who experienced early deterioration had significantly more severe baseline neurological deficit, higher prevalence of thalamic (66% vs 29%) and brain stem (73% vs 33%) lesions seen on baseline magnetic resonance imaging, and more often used concomitant dopamine receptor antagonists (46% vs 5%). Disease duration, treatment type (d-penicillamine or zinc sulfate), type of neurological manifestations, initial copper metabolism results, and liver function parameters did not differ between evaluated groups. CONCLUSIONS: Neurological worsening at the beginning of anti-copper therapy may occur in over 10% of WD patients. Special attention should be paid to those with severe initial neurological manifestations, advanced brain injury and using dopamine receptor antagonists. Type of anti-copper therapy did not show clear association with early neurological worsening.

Sunflower cataract: do not forget Wilson's disease.

A 41-year-old man with liver cirrhosis of unknown aetiology for 6 years was admitted to our department to confirm the diagnosis of Wilson's disease. He consulted an ophthalmologist who suspected the presence of a sunflower cataract and Kayser-Fleischer ring. At admission, his liver function tests were modestly impaired (Child-Pugh C, 10 pts). Neurological examination was normal, but cognitive functions were mildly impaired. Based on the copper metabolism abnormalities and clinical manifestation, we diagnosed Wilson's disease (Ferenci score, 6 pts) and started treatment with d-penicillamine. Presenting the case we would like to emphasise the significance of the ophthalmological examination in Wilson's disease diagnosis.

Measurement of urinary copper excretion after 48-h d-penicillamine cessation as a compliance assessment in Wilson's disease.

Treatment of Wilson's disease (WD) with anti-copper agents is effective in most compliant patients. During long-term treatment with chelating agents, a two-day interruption of the treatment should result in normal urinary copper concentrations (<50 µg/dl). The aim of this study was to establish the usefulness of this method as a compliance assessment in these patients. We examined consecutive patients treated with d-penicillamine (DPA) undergoing routine follow-up studies at our center. We performed 24-h urinary copper excretion analysis 48 h after interruption of chelating therapy. Thirty-two patients were enrolled. After DPA cessation, normalization of copper excretion was observed in 91% of reportedly compliant patients. The specificity and sensitivity values of this test were 87% and 77%, respectively. Measurement of 24-h urinary copper excretion after a 48-h interruption of DPA therapy in patients with WD is a reliable method for confirming patients' compliance.

Gene variants encoding proteins involved in antioxidant defense system and the clinical expression of Wilson disease.

BACKGROUND & AIMS: Wilson disease (WD) is an autosomal recessive disorder of copper metabolism resulting from pathogenic mutations of the ATP7B gene. The basis of phenotypic variability of the disease is not understood. The main mechanism of copper toxicity is probably related to generation of intracellular oxidative stress. To evaluate whether interindividual variability within genes encoding proteins involved in antioxidant defense system may modulate phenotypic expressions of WD. METHODS: Variability within genes encoding the cytosolic enzymes: glutathione peroxidase (GPX1 rs1050450) and manganese superoxide dismutase (SOD2 rs4880), and peroxisomal enzyme: catalase (CAT rs1001179) were analysed in 435 patients. Individual genotypes were tested for their relationship with phenotypic features of WD. RESULTS: GPX1 genotypes were not related to phenotypic manifestations of WD. Among males homozygocity for the SOD2 rs4880 T allele was related to earlier onset of WD. Patients homozygous for the CAT rs1001179 T allele characterized with later onset of WD [median (interquartile range) age: 29.0 (14.0) years vs. 22.0 (12.0) years, respectively, P < 0.004], later manifestation of hepatic symptoms [34.5 (14.0) years vs. 22.0 (12.0) years, P < 0.0009], and later presentation of neurological symptoms [37.0 (16.0) years vs. 28.0 (13.0) years, P < 0.03] than those having one or two C alleles. CONCLUSION: Variability within the CAT gene may be an important modifier of the clinical course of WD. SOD2 genotype may influence WD phenotype among males. These observations indirectly confirm a role of oxidative stress in the pathogenesis of WD, as well as indirectly suggest that peroxisomes impairment may be involved in WD pathophysiology.

Families with Wilson's disease in subsequent generations: clinical and genetic analysis.

INTRODUCTION: Wilson's disease is an inherited autosomal recessive disorder of copper metabolism. The prevalence of Wilson's disease in most populations is approximately 1 in 30,000. The risk for offspring is 0.5%. The aim of this study was to establish the frequency of disease among offspring of a cohort of Wilson's disease patients. MATERIALS AND METHODS: In February 2014, our registry included 760 cases of diagnosed Wilson's disease. We selected families in which Wilson's disease was diagnosed in the proband's offspring. RESULTS: Between 1957 and 2014, 1,050 relatives of affected members were screened. Wilson's disease in subsequent generations was observed in nine non-consanguineous families, with 12 affected offspring from nine probands. CONCLUSION: We detected a higher (4.08%) than expected (0.5%) frequency of Wilson's disease among proband offspring, which is in accordance with a recent genetic study in the United Kingdom that suggested a higher WD prevalence in the European population.

Symptomatic copper deficiency in three Wilson's disease patients treated with zinc sulphate.

Wilson's disease (WD) is caused by excess of copper that leads to accumulation of copper mainly in the liver, brain and needs life-long decoppering therapy. However, overtreatment with anti-copper agents may lead to copper deficiency which may cause neurological and hematological symptoms. Copper is an important cofactor for many enzymes. This report describes three WD patients with diagnosed copper deficiency during zinc sulphate (ZS) treatment. After 5-16 years of therapy all patients developed leucopenia. Spinal cord injury was manifested in two of the patients. One of them also presented myopathy. In conclusion, copper deficiency may occur in different time after treatment onset, therefore regular copper metabolism and hematological monitoring is necessary.

Congenital mirror movements: mutational analysis of RAD51 and DCC in 26 cases.

OBJECTIVE: We screened a large series of individuals with congenital mirror movements (CMM) for mutations in the 2 identified causative genes, DCC and RAD51. METHODS: We studied 6 familial and 20 simplex CMM cases. Each patient had a standardized neurologic assessment. Analysis of DCC and RAD51 coding regions included Sanger sequencing and a quantitative method allowing detection of micro rearrangements. We then compared the frequency of rare variants predicted to be pathogenic by either the PolyPhen-2 or the SIFT algorithm in our population and in the 4,300 controls of European origin on the Exome Variant Server. RESULTS: We found 3 novel truncating mutations of DCC that segregate with CMM in 4 of the 6 families. Among the 20 simplex cases, we found one exonic deletion of DCC, one DCC mutation leading to a frameshift, 5 missense variants in DCC, and 2 missense variants in RAD51. All 7 missense variants were predicted to be pathogenic by one or both algorithms. Statistical analysis showed that the frequency of variants predicted to be deleterious was significantly different between patients and controls (p < 0.001 for both RAD51 and DCC). CONCLUSION: Mutations and variants in DCC and RAD51 are strongly associated with CMM, but additional genes causing CMM remain to be discovered.