GDHS
MCID: GRD009
MIFTS: 40

Gordon Holmes Syndrome (GDHS)

Categories: Endocrine diseases, Genetic diseases, Mental diseases, Metabolic diseases, Neuronal diseases, Rare diseases, Reproductive diseases

Aliases & Classifications for Gordon Holmes Syndrome

MalaCards integrated aliases for Gordon Holmes Syndrome:

Name: Gordon Holmes Syndrome 56 12 25 73 36 29 6
Cerebellar Ataxia and Hypogonadotropic Hypogonadism 56 52 25 73 43 71
Lhrh Deficiency and Ataxia 56 12 52 25 73
Luteinizing Hormone-Releasing Hormone Deficiency with Ataxia 12 52 58
Cerebellar Ataxia-Hypogonadism Syndrome 12 52 58
Gdhs 56 12 73
Cahh 56 12 73
Deficiency of Luteinizing Hormone-Releasing Hormone with Ataxia 25 73
Gordon-Holmes Syndrome 52 58
Luteinizing Hormone-Releasing Hormone, Deficiency of, with Ataxia 56
Luteinizing Hormone Releasing Hormone, Deficiency of with Ataxia 52
Cerebellar Ataxia and Hypogonadotropic Hypogonadism; Cahh 56
Ataxia, Cerebellar, and Hypogonadotropic Hypogonadism 39
Cerebellar Ataxia - Hypogonadism 52

Characteristics:

Orphanet epidemiological data:

58
cerebellar ataxia-hypogonadism syndrome
Inheritance: Autosomal recessive; Age of onset: All ages;

OMIM:

56
Inheritance:
autosomal recessive


HPO:

31
gordon holmes syndrome:
Inheritance autosomal recessive inheritance


Classifications:

Orphanet: 58  
Rare neurological diseases
Rare infertility disorders
Rare gynaecological and obstetric diseases
Rare endocrine diseases


Summaries for Gordon Holmes Syndrome

Genetics Home Reference : 25 Gordon Holmes syndrome is a rare condition characterized by reproductive and neurological problems. One of the key features of the condition is reduced production of hormones that direct sexual development (hypogonadotropic hypogonadism). Many affected individuals have a delay in development of the typical signs of puberty, such as the growth of facial hair and deepening of the voice in males, and the start of monthly periods (menstruation) and breast development in females. Some never undergo puberty. While some people with Gordon Holmes syndrome seem to have normal puberty, they develop other problems with the reproductive system later in life. In early adulthood, individuals with Gordon Holmes syndrome develop neurological problems, usually beginning with speech difficulties (dysarthria). As the condition worsens, affected individuals have problems with balance and coordination (cerebellar ataxia), often leading to difficulties with activities of daily living and a need for wheelchair assistance. Some affected individuals also develop memory problems and a decline in intellectual function (dementia).

MalaCards based summary : Gordon Holmes Syndrome, also known as cerebellar ataxia and hypogonadotropic hypogonadism, is related to hypogonadism and pnpla6-related disorders, and has symptoms including cerebellar ataxia An important gene associated with Gordon Holmes Syndrome is RNF216 (Ring Finger Protein 216). Affiliated tissues include brain, breast and pituitary, and related phenotypes are neurological speech impairment and nystagmus

Disease Ontology : 12 An inherited metabolic disorder characterized by progressive cognitive decline, dementia, hypogonadotropic hypogonadism, and variable movement disorders resulting from disordered ubiquitination that has material basis in homozygous or compound heterozygous mutation in RNF216 on chromosome 7p22.1.

NIH Rare Diseases : 52 The following summary is from Orphanet , a European reference portal for information on rare diseases and orphan drugs. Orpha Number: 1173 Definition Cerebellar ataxia -hypogonadism syndrome is a very rare autosomal recessive neurodegenerative disorder characterized by the combination of progressive cerebellar ataxia with onset from early childhood to the fourth decade, and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). Cerebellar ataxia-hypogonadism syndrome belongs to a clinical continuum of neurodegenerative disorders along with clinically overlapping disorders such as ataxia-hypogonadism-choroidal dystrophy syndrome (see this term). Visit the Orphanet disease page for more resources.

OMIM : 56 Gordon Holmes syndrome 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). (212840)

KEGG : 36 Gordon Holmes syndrome (GHS) is an autosomal recessive adult-onset neurodegenerative disease characterized by cognitive decline, dementia, and other clinical features such as ataxia and hypogonadotropism. Multiple loss-of-function mutations in RNF216 gene have recently been identified in patients suffering from GHS.

UniProtKB/Swiss-Prot : 73 Gordon Holmes syndrome: A disease characterized by cerebellar symptoms and signs of sex steroid deficiency. Clinical features include cerebellar and brain stem atrophy, cerebellar ataxia, hypothalamic LHRH deficiency, hypogonadotrophic hypogonadism, lack of secondary sexual characteristics, and infertility.

Related Diseases for Gordon Holmes Syndrome

Graphical network of the top 20 diseases related to Gordon Holmes Syndrome:



Diseases related to Gordon Holmes Syndrome

Symptoms & Phenotypes for Gordon Holmes Syndrome

Human phenotypes related to Gordon Holmes Syndrome:

58 31 (show all 28)
# Description HPO Frequency Orphanet Frequency HPO Source Accession
1 neurological speech impairment 58 31 hallmark (90%) Very frequent (99-80%) HP:0002167
2 nystagmus 58 31 hallmark (90%) Very frequent (99-80%) HP:0000639
3 ataxia 58 31 hallmark (90%) Very frequent (99-80%) HP:0001251
4 abnormal electroretinogram 58 31 hallmark (90%) Very frequent (99-80%) HP:0000512
5 optic atrophy 58 31 hallmark (90%) Very frequent (99-80%) HP:0000648
6 abnormality of retinal pigmentation 58 31 hallmark (90%) Very frequent (99-80%) HP:0007703
7 hypogonadotrophic hypogonadism 58 31 hallmark (90%) Very frequent (99-80%) HP:0000044
8 decreased fertility 58 31 hallmark (90%) Very frequent (99-80%) HP:0000144
9 gynecomastia 58 31 hallmark (90%) Very frequent (99-80%) HP:0000771
10 abnormality of the hypothalamus-pituitary axis 58 31 hallmark (90%) Very frequent (99-80%) HP:0000864
11 muscular hypotonia 58 31 frequent (33%) Frequent (79-30%) HP:0001252
12 hemiplegia/hemiparesis 58 31 frequent (33%) Frequent (79-30%) HP:0004374
13 short stature 58 31 occasional (7.5%) Occasional (29-5%) HP:0004322
14 brachycephaly 58 31 occasional (7.5%) Occasional (29-5%) HP:0000248
15 clinodactyly of the 5th finger 58 31 occasional (7.5%) Occasional (29-5%) HP:0004209
16 dementia 58 31 occasional (7.5%) Occasional (29-5%) HP:0000726
17 supernumerary nipple 58 31 occasional (7.5%) Occasional (29-5%) HP:0002558
18 personality changes 58 31 occasional (7.5%) Occasional (29-5%) HP:0000751
19 oligomenorrhea 31 occasional (7.5%) HP:0000876
20 dysarthria 31 HP:0001260
21 behavioral abnormality 58 Occasional (29-5%)
22 abnormality of metabolism/homeostasis 31 HP:0001939
23 abnormality of the skeletal system 31 HP:0000924
24 hypogonadism 58 Very frequent (99-80%)
25 infertility 31 HP:0000789
26 cerebellar atrophy 31 HP:0001272
27 chorioretinal dystrophy 31 HP:0001135
28 cerebral atrophy 31 HP:0002059

Symptoms via clinical synopsis from OMIM:

56
Voice:
dysarthria

Neurologic Central Nervous System:
dementia
cerebellar atrophy
cerebral atrophy
cerebellar ataxia
chorea, prominent (in some patients)

Genitourinary Internal Genitalia Female:
amenorrhea, primary or secondary (in some patients)
oligomenorrhea (in some patients)

Endocrine Features:
hypogonadotrophic hypogonadism
secondary sexual characteristics lacking
hypothalamic and/or pituitary defect
gonadotropin response to exogenous luteinizing hormone releasing hormone (lhrh, in some patients)

Genitourinary Internal Genitalia Male:
no spontaneous puberty (in some patients)
small, soft testes (in some patients)

Clinical features from OMIM:

212840

UMLS symptoms related to Gordon Holmes Syndrome:


cerebellar ataxia

Drugs & Therapeutics for Gordon Holmes Syndrome

Search Clinical Trials , NIH Clinical Center for Gordon Holmes Syndrome

Cochrane evidence based reviews: cerebellar ataxia and hypogonadotropic hypogonadism

Genetic Tests for Gordon Holmes Syndrome

Genetic tests related to Gordon Holmes Syndrome:

# Genetic test Affiliating Genes
1 Gordon Holmes Syndrome 29 RNF216

Anatomical Context for Gordon Holmes Syndrome

MalaCards organs/tissues related to Gordon Holmes Syndrome:

40
Brain, Breast, Pituitary, Testes, Hypothalamus, Cerebellum, Skeletal Muscle

Publications for Gordon Holmes Syndrome

Articles related to Gordon Holmes Syndrome:

(show all 34)
# Title Authors PMID Year
1
RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder. 61 56 6
25841028 2015
2
Hypogonadotropic hypogonadism and cerebellar ataxia: detailed phenotypic characterization of a large, extended kindred. 61 56 6
11932290 2002
3
Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination. 56 6
23656588 2013
4
PNPLA6-Related Disorders 61 6
25299038 2014
5
Familial cerebellar ataxia and hypogonadotropic hypogonadism: evidence for hypothalamic LHRH deficiency. 61 56
6813427 1982
6
Congenital cerebellar hypoplasia and hypogonadotropic hypogonadism. 56
2243234 1990
7
FAMILIAL CEREBELLAR ATAXIA AND HYPOGONADISM. 56
14215172 1964
8
Familial hypogonadotrophic eunuchoidism with cerebellar ataxia. 56
13997834 1963
9
Mechanism and chain specificity of RNF216/TRIAD3, the ubiquitin ligase mutated in Gordon Holmes syndrome. 61
31087003 2019
10
RNF216 is essential for spermatogenesis and male fertility†. 61
30649198 2019
11
Gordon Holmes Syndrome Caused by RNF216 Novel Mutation in 2 Argentinean Siblings. 61
30949559 2019
12
Gordon Holmes syndrome due to compound heterozygosity of two new PNPLA6 variants - A diagnostic challenge. 61
30555943 2019
13
TRIAD3/RNF216 E3 ligase specifically synthesises K63-linked ubiquitin chains and is inactivated by mutations associated with Gordon Holmes syndrome. 61
30886743 2019
14
RNF216 Regulates the Migration of Immortalized GnRH Neurons by Suppressing Beclin1-Mediated Autophagy. 61
30733708 2019
15
Different Cerebellar Ataxia Phenotypes Associated with Mutations of the PNPLA6 Gene in Brazilian Patients with Recessive Ataxias. 61
29248984 2018
16
Rare case of Gordon Holmes syndrome. 61
29954774 2018
17
Establishment of STUB1/CHIP mutant induced pluripotent stem cells (iPSCs) from a patient with Gordon Holmes syndrome/SCAR16. 61
29679845 2018
18
Sir Gordon Morgan Holmes (1876-1965): one of the founders of modern neurology. 61
29116546 2018
19
Gordon Holmes syndrome: finally genotype meets phenotype. 61
28972031 2017
20
TRIAD3/RNF216 mutations associated with Gordon Holmes syndrome lead to synaptic and cognitive impairments via Arc misregulation. 61
27995769 2017
21
STUB1/CHIP mutations cause Gordon Holmes syndrome as part of a widespread multisystemic neurodegeneration: evidence from four novel mutations. 61
28193273 2017
22
Phenotypic spectrum of POLR3B mutations: isolated hypogonadotropic hypogonadism without neurological or dental anomalies. 61
27512013 2017
23
Ataxia and Hypogonadotropic Hypogonadism with Intrafamilial Variability Caused by RNF216 Mutation. 61
27441066 2016
24
SKELETAL MUSCLE MITOCHONDRIAL ALTERATIONS IN CARBOXYL TERMINUS OF HSC70 INTERACTING PROTEIN (CHIP) -/- MICE. 61
28593200 2016
25
Mutations in RNF216 do not cause 4H syndrome. 61
26365775 2015
26
Neuropathy target esterase impairments cause Oliver-McFarlane and Laurence-Moon syndromes. 61
25480986 2015
27
The clinical spectrum of inherited diseases involved in the synthesis and remodeling of complex lipids. A tentative overview. 61
25413954 2015
28
Delayed Induction of Human NTE (PNPLA6) Rescues Neurodegeneration and Mobility Defects of Drosophila swiss cheese (sws) Mutants. 61
26671664 2015
29
Inborn errors of metabolism in the biosynthesis and remodelling of phospholipids. 61
25178427 2015
30
Loss-of-function mutations in PNPLA6 encoding neuropathy target esterase underlie pubertal failure and neurological deficits in Gordon Holmes syndrome. 61
25033069 2014
31
Ataxia and hypogonadism caused by the loss of ubiquitin ligase activity of the U box protein CHIP. 61
24113144 2014
32
PNPLA6 mutations cause Boucher-Neuhauser and Gordon Holmes syndromes as part of a broad neurodegenerative spectrum. 61
24355708 2014
33
The gonadotropin-releasing hormone type I receptor is expressed in the mouse cerebellum. 61
18592335 2008
34
Autosomal recessive syndrome of cerebellar ataxia and hypogonadotropic hypogonadism. 61
1149314 1975

Variations for Gordon Holmes Syndrome

ClinVar genetic disease variations for Gordon Holmes Syndrome:

6 ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎ ‎‎
# Gene Name Type Significance ClinVarId dbSNP ID GRCh37 Pos GRCh38 Pos
1 RNF216 NM_207111.4(RNF216):c.1367G>A (p.Gly456Glu)SNV Pathogenic 199654 rs794728000 7:5769085-5769085 7:5729454-5729454
2 RNF216 NM_207111.4(RNF216):c.904C>T (p.Gln302Ter)SNV Pathogenic 199655 rs373785974 7:5780744-5780744 7:5741113-5741113
3 RNF216 NM_207111.4(RNF216):c.1616A>G (p.Tyr539Cys)SNV Pathogenic 199656 rs148642312 7:5760692-5760692 7:5721061-5721061
4 RNF216 NM_207111.4(RNF216):c.2251C>T (p.Arg751Cys)SNV Pathogenic 50912 rs387907368 7:5680916-5680916 7:5641285-5641285
5 RNF216 NM_207111.4(RNF216):c.1791T>A (p.Cys597Ter)SNV Pathogenic 50913 rs387907369 7:5754726-5754726 7:5715095-5715095
6 RNF216 NM_207111.4(RNF216):c.613_614GA[1] (p.Glu205fs)short repeat Pathogenic 50914 rs387907370 7:5781032-5781033 7:5741401-5741402
7 RNF216 NM_207111.4(RNF216):c.202-1G>CSNV Pathogenic 587594 rs1562451985 7:5781447-5781447 7:5741816-5741816
8 RNF216 NM_207111.4(RNF216):c.2663T>A (p.Val888Glu)SNV Uncertain significance 800990 7:5662600-5662600 7:5622969-5622969
9 RNF216 NM_207111.4(RNF216):c.2686G>T (p.Val896Phe)SNV Uncertain significance 802289 7:5662577-5662577 7:5622946-5622946

UniProtKB/Swiss-Prot genetic disease variations for Gordon Holmes Syndrome:

73
# Symbol AA change Variation ID SNP ID
1 RNF216 p.Arg660Cys VAR_070048 rs133521537
2 RNF216 p.Arg694Cys VAR_070049 rs387907368

Expression for Gordon Holmes Syndrome

Search GEO for disease gene expression data for Gordon Holmes Syndrome.

Pathways for Gordon Holmes Syndrome

GO Terms for Gordon Holmes Syndrome

Cellular components related to Gordon Holmes Syndrome according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 membrane raft GO:0045121 8.62 RIPK1 ARC

Biological processes related to Gordon Holmes Syndrome according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 protein homooligomerization GO:0051260 8.96 RIPK1 ARC
2 proteasome-mediated ubiquitin-dependent protein catabolic process GO:0043161 8.62 STUB1 RNF216

Molecular functions related to Gordon Holmes Syndrome according to GeneCards Suite gene sharing:

# Name GO ID Score Top Affiliating Genes
1 ubiquitin protein ligase activity GO:0061630 8.62 STUB1 RNF216

Sources for Gordon Holmes Syndrome

3 CDC
7 CNVD
9 Cosmic
10 dbSNP
11 DGIdb
17 EFO
18 ExPASy
19 FMA
28 GO
29 GTR
30 HMDB
31 HPO
32 ICD10
33 ICD10 via Orphanet
34 ICD9CM
35 IUPHAR
36 KEGG
37 LifeMap
39 LOVD
41 MedGen
43 MeSH
44 MESH via Orphanet
45 MGI
48 NCI
49 NCIt
50 NDF-RT
53 NINDS
54 Novoseek
56 OMIM
57 OMIM via Orphanet
61 PubMed
63 QIAGEN
68 SNOMED-CT via HPO
69 TGDB
70 Tocris
71 UMLS
72 UMLS via Orphanet
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