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Cerebellar ataxia-hypogonadism syndrome(GDHS; CAHH)

MedGen UID:
349137
•Concept ID:
C1859305
•
Disease or Syndrome
Synonyms: Cerebellar ataxia and hypogonadotropic hypogonadism; Cerebellar ataxia hypogonadotropic hypogonadism; Gordon Holmes syndrome; LHRH DEFICIENCY AND ATAXIA; Luteinizing hormone releasing hormone, deficiency of with ataxia
SNOMED CT: Progressive cerebellar ataxia with hypogonadism (230240004); Luteinizing hormone-releasing hormone deficiency with ataxia (230240004); Gordon Holmes syndrome (230240004)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
•Concept ID:
C0441748
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal recessive inheritance (Orphanet)
 
Gene (location): RNF216 (7p22.1)
 
Monarch Initiative: MONDO:0008935
OMIM®: 212840
Orphanet: ORPHA1173

Disease characteristics

Excerpted from the GeneReview: PNPLA6 Disorders
PNPLA6 disorders span a phenotypic continuum characterized by variable combinations of cerebellar ataxia; upper motor neuron involvement manifesting as spasticity and/or brisk reflexes; chorioretinal dystrophy associated with variable degrees of reduced visual function; and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). The hypogonadotropic hypogonadism occurs either in isolation or as part of anterior hypopituitarism (growth hormone, thyroid hormone, or gonadotropin deficiencies). Common but less frequent features are peripheral neuropathy (usually of axonal type manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting); hair anomalies (long eyelashes, bushy eyebrows, or scalp alopecia); short stature; and impaired cognitive functioning (learning disabilities in children; deficits in attention, visuospatial abilities, and recall in adults). Some of these features can occur in distinct clusters on the phenotypic continuum: Boucher-Neuhäuser syndrome (cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism); Gordon Holmes syndrome (cerebellar ataxia, hypogonadotropic hypogonadism, and – to a variable degree – brisk reflexes); Oliver-McFarlane syndrome (trichomegaly, chorioretinal dystrophy, short stature, intellectual disability, and hypopituitarism); Laurence-Moon syndrome; and spastic paraplegia type 39 (SPG39) (upper motor neuron involvement, peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia). [from GeneReviews]
Full text of GeneReview (by section):
Summary  |  GeneReview Scope  |  Diagnosis  |  Clinical Characteristics  |  Genetically Related (Allelic) Disorders  |  Differential Diagnosis  |  Management  |  Genetic Counseling  |  Resources  |  Molecular Genetics  |  Chapter Notes  |  References
Authors:
Matthis Synofzik  |  Robert B Hufnagel  |  Stephan Züchner   view full author information

Additional descriptions

From OMIM
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).  http://www.omim.org/entry/212840
From MedlinePlus Genetics
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).  https://medlineplus.gov/genetics/condition/gordon-holmes-syndrome

Clinical features

From HPO
Infertility
MedGen UID:
43876
•Concept ID:
C0021359
•
Finding
Inability to conceive for at least one year after trying and having unprotected sex. Causes of female infertility include endometriosis, fallopian tubes obstruction, and polycystic ovary syndrome. Causes of male infertility include abnormal sperm production or function, blockage of the epididymis, blockage of the ejaculatory ducts, hypospadias, exposure to pesticides, and health related issues.
See: Feature record | Search on this feature
Oligomenorrhea
MedGen UID:
18159
•Concept ID:
C0028949
•
Pathologic Function
Infrequent menses (less than 6 per year or more than 35 days between cycles).
See: Feature record | Search on this feature
Cerebellar ataxia
MedGen UID:
849
•Concept ID:
C0007758
•
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- or overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
See: Feature record | Search on this feature
Dysarthria
MedGen UID:
8510
•Concept ID:
C0013362
•
Mental or Behavioral Dysfunction
Dysarthric speech is a general description referring to a neurological speech disorder characterized by poor articulation. Depending on the involved neurological structures, dysarthria may be further classified as spastic, flaccid, ataxic, hyperkinetic and hypokinetic, or mixed.
See: Feature record | Search on this feature
Cerebral atrophy
MedGen UID:
116012
•Concept ID:
C0235946
•
Disease or Syndrome
Atrophy (wasting, decrease in size of cells or tissue) affecting the cerebrum.
See: Feature record | Search on this feature
Dementia
MedGen UID:
99229
•Concept ID:
C0497327
•
Mental or Behavioral Dysfunction
A loss of global cognitive ability of sufficient amount to interfere with normal social or occupational function. Dementia represents a loss of previously present cognitive abilities, generally in adults, and can affect memory, thinking, language, judgment, and behavior.
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Cerebellar atrophy
MedGen UID:
196624
•Concept ID:
C0740279
•
Disease or Syndrome
Cerebellar atrophy is defined as a cerebellum with initially normal structures, in a posterior fossa with normal size, which displays enlarged fissures (interfolial spaces) in comparison to the foliae secondary to loss of tissue. Cerebellar atrophy implies irreversible loss of tissue and result from an ongoing progressive disease until a final stage is reached or a single injury, e.g. an intoxication or infectious event.
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Abnormality of the skeletal system
MedGen UID:
867418
•Concept ID:
C4021790
•
Anatomical Abnormality
An abnormality of the skeletal system.
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Abnormality of metabolism/homeostasis
MedGen UID:
867398
•Concept ID:
C4021768
•
Finding
See: Feature record | Search on this feature
Hypogonadotropic hypogonadism
MedGen UID:
82883
•Concept ID:
C0271623
•
Disease or Syndrome
Hypogonadotropic hypogonadism is characterized by reduced function of the gonads (testes in males or ovaries in females) and results from the absence of the gonadal stimulating pituitary hormones
See: Feature record | Search on this feature
Chorioretinal dystrophy
MedGen UID:
346626
•Concept ID:
C1857627
•
Disease or Syndrome
See: Feature record | Search on this feature
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Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVCerebellar ataxia-hypogonadism syndrome

Recent clinical studies

Etiology

A novel PNPLA6 mutation in a Turkish family with intractable Holmes tremor and spastic ataxia.
Emekli AS, Samanci B, Şimşir G, Hanagasi HA, Gürvit H, Bilgiç B, Başak AN
Neurol Sci 2021 Apr;42(4):1535-1539. Epub 2020 Nov 18 doi: 10.1007/s10072-020-04869-6. PMID: 33210227

Diagnosis

A novel PNPLA6 mutation in a Turkish family with intractable Holmes tremor and spastic ataxia.
Emekli AS, Samanci B, Şimşir G, Hanagasi HA, Gürvit H, Bilgiç B, Başak AN
Neurol Sci 2021 Apr;42(4):1535-1539. Epub 2020 Nov 18 doi: 10.1007/s10072-020-04869-6. PMID: 33210227
Boucher Neuhäuser Syndrome - A rare cause of inherited hypogonadotropic hypogonadism. A case of two adult siblings with two novel mutations in PNPLA6.
Langdahl JH, Frederiksen AL, Nguyen N, Brusgaard K, Juhl CB
Eur J Med Genet 2017 Feb;60(2):105-109. Epub 2016 Nov 16 doi: 10.1016/j.ejmg.2016.11.003. PMID: 27866050
Cerebellar ataxia associated with hypogonadotropic hypogonadism and chorioretinopathy: a poorly recognized association.
Erdem E, Kiratli H, Erbaş T, Varli K, Eldem B, Akalin S, Tan E, Topaloglu H, Gedikoglu G
Clin Neurol Neurosurg 1994 Feb;96(1):86-91. doi: 10.1016/0303-8467(94)90036-1. PMID: 8187389

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