Alternative titles; symbols
SNOMEDCT: 230240004; ORPHA: 1173; DO: 0111587;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 7p22.1 | Cerebellar ataxia and hypogonadotropic hypogonadism | 212840 | Autosomal recessive | 3 | RNF216 | 609948 |
A number sign (#) is used with this entry because of evidence that Gordon Holmes syndrome (GDHS) is caused by homozygous or compound heterozygous mutation in the RNF216 gene (609948) on chromosome 7p22.
Gordon Holmes syndrome (GDHS) is an autosomal recessive adult-onset neurodegenerative disorder characterized by progressive cognitive decline, dementia, and variable movement disorders, such as ataxia and chorea. The neurologic phenotype is associated with hypogonadotropic hypogonadism (summary by Santens et al., 2015).
Holmes (1907) first described the association of cerebellar ataxia and hypogonadism. He reported 3 brothers and 1 sister who, in their mid-thirties, developed cerebellar symptoms and signs of sex steroid deficiency. As gonadotropin assays were developed, both hypo- and hypergonadotropic forms were reported. The hypogonadism of most patients with Gordon Holmes syndrome is hypogonadotropic, with a defect in the production or release of gonadotropins by the pituitary gland (Seminara et al., 2002).
The cases of Volpe et al. (1963) had eunuchoid skeletal features and low urinary gonadotropins with the additional feature of cerebellar ataxia. Matthews and Rundle (1964) described 2 brothers with pure cerebellar ataxia beginning at about 20 years of age and associated with marked hypogonadism due apparently to low gonadotropin excretion. One brother had moderate nerve deafness and developed dementia.
Conclusive evidence of autosomal recessive inheritance was presented also by Berciano et al. (1982) who observed affected brother and sister with consanguineous parents. One of the patients developed dementia. They demonstrated, furthermore, that the hypogonadotropism was due to deficiency of hypothalamic LHRH (luteinizing hormone-releasing hormone; LHRH; 152760); raised gonadotropin levels were found after repeated stimulation with exogenous LHRH. CT scan in 1 case showed cerebellar and brainstem atrophy.
Abs et al. (1990) described a 20-year-old male with longstanding, nonprogressive ataxia due to hypoplasia of the inferior cerebellar vermis. He also showed hypogonadism with low serum gonadotropin and prolactin levels, which were judged to be due to a primary deficiency of the gonadotroph and lactotroph cells, rather than a hypothalamic lesion, because of the response to administration of gonadotropin-releasing hormone. The patient was born from an incestuous relationship between a brother and sister.
Seminara et al. (2002) described the largest kindred with Gordon Holmes syndrome characterized to that time. The parents of the 3 affected sibs were first cousins, suggesting that the disease was inherited as an autosomal recessive trait. The sibs' initial evaluation was notable for low serum levels of sex steroids and gonadotropins (consistent with hypogonadotropic hypogonadism), progressive ataxia, and dementia. Extended treatment with physiologic doses of pulsatile GNRH (LHRH) failed to stimulate a gonadotropin response. Brain imaging revealed volume loss in the cerebellum, with extensive abnormalities in the cerebral white matter.
Clinical Variability
Santens et al. (2015) reported sibs from 2 unrelated Belgian families with a variant of Gordon Holmes syndrome presenting as a Huntington disease (HD; 143100)-like disorder. In the first family, 2 sibs presented in their thirties with personality changes and inappropriate behavior associated with choreic movements of the face and limbs. They had brisk reflexes and cerebellar signs, including dysmetria, ataxia, unsteady gait, dysdiadochokinesis, and dysarthria. The disorder was progressive, and both patients showed impulsivity and aggressive behavior at times. One sib had significant deterioration, with widespread cognitive dysfunction and loss of speech; she became bedridden and died of aspiration pneumonia in her forties. The other sib showed progressive decline and resided in an institution. Brain imaging of both sibs showed cortical atrophy, pronounced cerebellar degeneration, diffuse white matter lesions in the cerebrum and cerebellum, and atrophy of the putamen. In the second family, 2 sibs presented at age 49 years with mild chorea and progressive memory problems. Brain imaging showed white matter lesions in the cerebrum and brainstem. Their mother presented with late-onset progressive dementia and parkinsonism at age 71. Three of the 4 sibs were found to have laboratory evidence of hypogonadotropic hypogonadism. Santens et al. (2015) emphasized the prominent chorea in these patients and noted that hypogonadism had not been suspected clinically, thus expanding the phenotypic spectrum of GDHS.
The transmission pattern of Gordon Holmes syndrome in the families reported by Santens et al. (2015) was consistent with autosomal recessive inheritance.
In a 7-generation consanguineous Palestinian family with ataxia and hypogonadotropic hypogonadism, originally reported by Seminara et al. (2002), Margolin et al. (2013) performed exome sequencing and identified homozygosity for 2 missense mutations in 2 different genes, RNF216 (R751C; 609948.0001) and OTUD4 (G333V; 611744.0001). The mutations segregated with disease in the family, and neither was found in 672 Middle Eastern control chromosomes, including 36 Palestinian chromosomes; the OTUD4 G333V mutation was, however, detected in 2 of 13,006 chromosomes from the NHLBI Exome Sequencing Project. Sequencing of the RNF216 and OTUD4 genes in 9 more affected individuals from 7 families revealed no further mutations in OTUD4; however, 1 proband was compound heterozygous for 2 truncating mutations in the RNF216 gene (609948.0002-609948.0003). In addition, 3 probands carried heterozygous RNF216 mutations, but the latter mutations were also detected in parents and sibs. Margolin et al. (2013) suggested that oligogenic inheritance would be the most parsimonious explanation for the observed patterns.
In affected sibs from 2 unrelated Belgian families with a variant of Gordon Holmes syndrome, Santens et al. (2015) identified homozygous or compound heterozygous mutations in the RNF216 gene (609948.0004-609948.0006). The mutation in the first family, which was consanguineous, was found by a combination of homozygosity mapping and whole-exome sequencing. The mother in the second family, who had late-onset dementia and parkinsonism, was heterozygous for 1 of the mutations. Functional studies of the variants were not performed.
Margolin et al. (2013) studied 8 patients with cerebellar ataxia and hypogonadotropic hypogonadism, 3 of whom were sibs from a consanguineous Palestinian family originally reported by Seminara et al. (2002). The 8 patients, all of whom carried mutations in the RNF216 gene, had similar clinical histories, presenting in adolescence or early adulthood with hypogonadotropic hypogonadism due to defects at the hypothalamic and pituitary levels of the reproductive endocrine axis, but no other pituitary abnormalities. Dysarthria was the initial neurologic symptom in some patients, but ataxia developed in all patients, leading to wheelchair dependency and to bed confinement for some. Dementia was also prominent, with personality changes and memory loss occurring at the onset of disease, followed by mutism and uncoordinated, purposeless movements during the end stages. Neurologic imaging revealed striking similarities, with cerebellar and cortical atrophy but no abnormalities of the pituitary gland. Another 4 patients with ataxia and hypogonadotropic hypogonadism, who did not have mutations in the RNF216 gene, did not develop dementia, and no cause for their ataxia was discovered despite extensive evaluation. Three of the latter patients displayed oculomotor abnormalities, including nystagmus and ophthalmoplegia, features that were not seen in any of the patients with RNF216 mutations.
Abs, R., Van Vleymen, E., Parizel, P. M., Van Acker, K., Martin, M., Martin, J.-J. Congenital cerebellar hypoplasia and hypogonadotropic hypogonadism. J. Neurol. Sci. 98: 259-265, 1990. [PubMed: 2243234] [Full Text: https://doi.org/10.1016/0022-510x(90)90267-q]
Berciano, J., Amado, J. A., Freijanes, J., Rebollo, M., Vaquero, A. Familial cerebellar ataxia and hypogonadotropic hypogonadism: evidence for hypothalamic LHRH deficiency. J. Neurol. Neurosurg. Psychiat. 45: 747-751, 1982. [PubMed: 6813427] [Full Text: https://doi.org/10.1136/jnnp.45.8.747]
Bernard-Weil, E., Endtz, L. J. Sur un cas familial de degeneration spino-cerebelleuse avec eunuchoidisme hypogonadotrophique: considerations pathogeniques et methodologiques. Nouv. Presse Med. 70: 524-526, 1962.
Holmes, G. A form of familial degeneration of the cerebellum. Brain 30: 466-489, 1907.
Margolin, D. H., Kousi, M., Chan, Y.-M., Lim, E. T., Schmahmann, J. D., Hadjivassiliou, M., Hall, J. E., Adam, I., Dwyer, A., Plummer, L., Aldrin, S. V., O'Rourke, J., and 9 others. Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. New Eng. J. Med. 368: 1992-2003, 2013. [PubMed: 23656588] [Full Text: https://doi.org/10.1056/NEJMoa1215993]
Matthews, W. B., Rundle, A. T. Familial cerebellar ataxia and hypogonadism. Brain 87: 463-468, 1964. [PubMed: 14215172] [Full Text: https://doi.org/10.1093/brain/87.3.463]
Santens, P., Van Damme, T., Steyaert, W., Willaert, A., Sablonniere, B., De Paepe, A., Coucke, P. J., Dermaut, B. RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder. Neurology 84: 1760-1766, 2015. [PubMed: 25841028] [Full Text: https://doi.org/10.1212/WNL.0000000000001521]
Seminara, S. B., Acierno, J. S., Jr., Abdulwahid, N. A., Crowley, W. F., Jr., Margolin, D. H. Hypogonadotropic hypogonadism and cerebellar ataxia: detailed phenotypic characterization of a large, extended kindred. J. Clin. Endocr. Metab. 87: 1607-1612, 2002. [PubMed: 11932290] [Full Text: https://doi.org/10.1210/jcem.87.4.8384]
Volpe, R., Metzler, W. S., Johnston, M. W. Familial hypogonadotrophic eunuchoidism with cerebellar ataxia. J. Clin. Endocr. Metab. 23: 107-115, 1963. [PubMed: 13997834] [Full Text: https://doi.org/10.1210/jcem-23-1-107]