Cerebellar ataxia-hypogonadism syndrome is a neurodegenerative disorder that may also patients to as Gordon Holmes syndrome (GHS). In children and adolescents, delays in the development of secondary sexual characteristics may be observed. Movement disorders due to cerebellar degeneration are generally presented years later, and they may be accompanied by progressive dementia. The pathogenesis of GHS is poorly understood, and treatment is largely limited to supportive care. Distinct mutations have been related to GHS, and the mode of inheritance is likely to be autosomal recessive irrespective of the underlying gene defect.
The presentation of GHS is highly heterogeneous. First symptoms may manifest at any time between infancy and mid-adulthood, with symptoms of hypogonadotropic hypogonadism generally preceding those of neurodegeneration. In rare cases, ataxia and other symptoms of cerebellar degeneration may manifest in infancy, when hypogonadism has not yet become symptomatic .
With regard to GHS-related hypogonadism, delays in the development of secondary sexual characteristics are most commonly observed. Reduced or absent growth of body hair may be noted in boys and girls, and this condition may be accompanied by lack of beard growth and maintenance of a high-pitched voice in males. Penile growth may be delayed as well as testicular development, and the body habitus may become eunuchoid . Female patients may show poor breast development and primary or, less frequently, secondary amenorrhea . Delays in uterine and ovarian development are to be expected and may be confirmed sonographically . In case of mild symptoms, patients may not seek medical advice until adulthood, when sexual dysfunctions or infertility interfere with intimate relationships and family planning  .
Symptoms and signs of cerebellar disease aren't typically noted before early or mid-adulthood. Patients may present with a staggering gait, incoordination of the upper extremities, and dysarthric speech . Tremor and choreiform movements of the head and limbs may also be observed. Nystagmus is a common feature of GHS, while sensory perception remains unaltered . Some patients may eventually show personality changes, become increasingly withdrawn, and develop dementia   .
Entire Body System
- Normal Hearing
The audiogram showed normal hearing. [scielo.br]
The audiogram showed normal hearing. LHRH stimulation test showed low baseline LH and FSH without response. [jmg.bmj.com]
Pure tone audiogram showed normal hearing. Echocardiogram and electrocardiogram were normal. Multimodal evoked potential studies and nerve conduction studies were normal. Karyotype was 46, XX. [pediatricneurosciences.com]
- Primary Amenorrhea
DISCUSSION This case illustrates a condition characterized by adult onset ataxia, primary amenorrhea, hypergonadotropic hypogonadism, psychomotor retardation and pigmentary retinopathy. [scielo.br]
Ten patients had primary amenorrhea. We ruled out the ataxia with vitamin E deficiency which is commoner and treatable cause of early onset of cerebellar ataxia with cerebellar atrophy. [pediatricneurosciences.com]
amenorrhea Nystagmus Hearing impairment Intellectual disability Gait ataxia CNS hypomyelination Intention tremor Rare Symptoms - Less than 30% cases Seizures Frequent falls Dysdiadochokinesis Dysmetria Generalized hypotonia Global developmental delay [mendelian.co]
amenorrhea Progeria Pseudoachondroplastic Form of Spondyloepiphyseal Pseudoxanthoma Elasticum Puberty Pure precocious thelarche Pure premature adrenarche Pure premature adrenarche of infancy Pyknodysostosis of Maroteaux and Lamy Pyle's Disease (R) Radial [koreapediatrics.com]
Hypogonadotropic hypogonadism is generally diagnosed by means of endocrine analyses. The levels of both FSH and LH are decreased, which implies low levels of testosterone and estradiol in males and females, respectively. The identification of the underlying pathology remains a major challenge, though, and the diagnosis of GHS is not generally made before the onset of neurodegenerative symptoms. A family history of GHS would provide an important clue to this end but is rarely documented. Thus, in clinical practice, it's the unusual combination of cerebellar ataxia and hypogonadotropic hypogonadism that finally raises suspicion as to GHS, prompting neuroimaging and genetic studies .
Due to the delayed onset of neurological symptoms, magnetic resonance imaging is not usually carried out during the initial stages of the disease. Accordingly, little is known about the time course of brain damage in GHS patients. Neurological deficits as observed in later stages of the disease are typically induced by cortical atrophy, pronounced cerebellar degeneration, and diffuse white matter lesions in the cerebrum and cerebellum  . Most patients with visible brain changes do show cognitive deficits, but they may be subtle, and their detection may require the application of highly sensitive screening methods .
Genetic studies should be realized to identify the underlying mutation, to facilitate the familial workup, and to add to the limited data currently available on GHS. The latter is of particular importance to elucidate genotype-phenotype correlations, since, to date, the deduction of a prognosis from the molecular biological findings remains problematic . What's more, genetic abnormalities may not be found in some patients, and GHS essentially continues to be a clinical diagnosis .
The administration of gonadotropin-releasing hormone may initially prompt the release of sex hormones, but the pituitary response has been reported to diminish over time  . Moreover, some patients never respond to treatment with gonadotropin-releasing hormone .
Alternatively, chorionic gonadotropin, menotropins, testosterone, or estrogen and progesterone may be administered to compensate for the deficit of gonadotropin-releasing hormone. Beyond that, calcium and vitamin D supplementation may be considered in women. The patients' response to treatment varies largely, though, and individual adjustments are to be made. Although an improvement of secondary sexual characteristics may be observed within months of therapy, renewed deterioration is highly likely .
With regards to GHS-related neurodegeneration, no effective treatment is known. Supportive care should be offered, and patients may benefit from physiotherapy exercises, speech and swallowing therapy .
GHS follows a progressive course and is associated with persistent cognitive decline and loss of motor skills. Patients tend to lose ambulation and their ability to cope with everyday life, become confined to bed, and eventually succumb to the disease. From the time of diagnosis, patients often survive for more than a decade  . Aspiration pneumonia is a common cause of death of GHS patients .
GHS has been related to mutations in genes PNPLA6, RNF216 and/or OTUD4. Patients may be homozygous for inactivating mutations of PNPLA6 or RNF216, or they may carry a combination of mutations in RNF216 and OTUD4 . These genotypic differences are known to result in distinct phenotypes: While PNPLA6-related GHS is not typically accompanied by dementia, the latter is a common feature in those with pathogenic variants of RNF216 . It should be noted, too, that mutations in the aforementioned genes may possibly cause diseases other than GHS. In this context, mutations in PNPLA6 have been linked to Laurence-Moon syndrome, Oliver-McFarlane syndrome, Boucher-Neuhäuser syndrome, and spastic paraplegia type 39 .
Additionally, mutations of the STUB1 gene have been determined in GHS patients . STUB1 mutations are generally associated with autosomal recessive spinocerebellar ataxia type 16 (SCAR16), but there is considerable phenotypic overlap and GHS has recently been postulated to be part of a broader spectrum of SCAR16 phenotypes .
Both the genetic heterogeneity of GHS and the differential phenotypic effects of disease-causing mutations speak in favor of a complex molecular background of neurodegeneration associated with ataxia and hypogonadism. GHS has first been described more than a century ago, when it could not yet be related to any of the genes named in this paragraph, and the diagnosis has since been based on clinical features. An increasingly better understanding of the causes and progression of GHS-like disorders may eventually give rise to a new classification scheme and diagnostic guidelines.
The disease is inherited in an autosomal recessive manner and has mainly been diagnosed in consanguineous families   . Heterozygous carriers of GHS-related mutations have not yet been described to present any symptoms, which is consistent with most patients having a negative family history. Data regarding the incidence and prevalence of GHS are not available, but they are assumed to be low: In a large study comprising 1,500 patients with progressive cerebellar ataxia, only one has been diagnosed with GHS  .
The pathogenesis of GHS remains incompletely understood. Some hypotheses have been derived from the function of genes implied in the etiology of GHS:
- PNPLA6 encodes for a phospholipase that deacetylates intracellular phosphatidylcholine to produce glycerophosphocholine. This phospholipase is thought to play a major role in neuronal differentiation and the maintenance of membrane stability. In this context, pathogenic mutations of PNPLA6 may result in abnormal concentrations of phosphatidylcholine in neuronal membranes, thereby affecting brain development and function.
- On the other hand, RNF216 encodes for a protein involved in the ubiquitin-proteasome system. It acts as an E3 ubiquitin ligase, marking proteins as substrates for degradation within the proteasome. Inactivating mutations of RNF216, like those described in GHS patients, entail deficiencies in the breakdown of proteins and the accumulation of Arc and other substrates in neurons. Eventually, these may interfere with synaptic function and plasticity .
Neither gene defect could yet be related to the localized neurodegeneration characteristic of GHS. What's more, GHS-related hypogonadotropic hypogonadism may derive from either hypothalamic or pituitary dysfunction . Some patients initially respond to stimulation by gonadotropin-releasing hormone, but such treatment loses efficacy over time. In line with these observations, both the hypothalamus and pituitary gland have been assumed to undergo degenerative changes.
Families known to harbor mutations that result in GHS may benefit from genetic counseling. For this, however, it is necessary to identify these mutations. The thorough workup of GHS cases is an absolute prerequisite to advise family members, to identify carriers, and to carry out prenatal diagnosis . Beyond that, the avoidance of consanguineous marriage may largely contribute to the prevention of GHS and other hereditary disorders, and the general public should be informed accordingly.
Hereditary ataxias are a heterogeneous group of disorders, and patients tend to present both neurological and non-neurological signs and symptoms  . The association of cerebellar ataxia and hypogonadism, characteristic of GHS, was
first recognized as a distinct syndrome in 1907. Affected individuals show variable movement disorders such as ataxia and chorea and generally have a medical history consistent with hypogonadotropic hypogonadism. The disease follows a progressive course and is associated with ongoing cognitive decline and loss of motor skills. Patients become increasingly helpless and in need of care.
The limited understanding of the disease' pathogenesis has so far prevented the development of effective treatments. While hormone replacement therapy may provide some relief of endocrine symptoms, neurodegenerative processes can neither be halted nor delayed. As of today, GHS is universally fatal, leading to death within several years after the onset of movement disorders and cognitive impairment. Additional research is required to better understand the pathophysiological background of GHS-associated neurodegeneration and to be able to intervene in a target-oriented, rather than symptomatic manner.
Cerebellar ataxia-hypogonadism syndrome is a rare disease that is also referred to as Gordon-Holmes syndrome (GHS). Even though the causes of GHS remain incompletely understood, it is known to be a hereditary disorder. Children who inherit certain gene defects from both of their parents may develop GHS, which is why parental consanguinity increases the risk of this syndrome.
Hypogonadism refers to endocrine dysfunctions resulting in decreased activity of the testes or ovaries, which is reflected in low levels of gonadotropins FHS and LH, as well as testosterone and estradiol. This condition commonly entails delays in the development of secondary sexual characteristics. These features - which comprise the growth of body hair and beard, the growth of penis, testicles, and female breasts, as well as the onset of menstruation - are expected to appear during puberty, but may be much less pronounced in GHS patients or even be absent.
The causes of GHS-related hypogonadism are rarely identified before the onset of additional symptoms: The disease follows a progressive course and is typically associated with gait disturbance, incoordination of the arms and hands, and speaking difficulties from early or mid-adulthood. Repetitive and rapid, jerky, involuntary movements are common in advanced GHS, as are nystagmus, personality changes, and mild cognitive impairment to dementia.
The common denominator of hypogonadism and movement disorders is the progressive loss of neurons. Imaging studies reveal profound changes in the central nervous system, such as cortical atrophy and cerebellar degeneration, which eventually lead to loss of ambulation and independence, need for care, and death. Hormone replacement therapy may be provided to alleviate symptoms associated with hypogonadism, but no effective treatment is known to halt or delay the neurocognitive decline.
In order to confirm a tentative diagnosis of GHS, genetic analyses have to be carried out. What's more, the determination of the underlying gene defects facilitates the family workup, the identification of asymptomatic carriers, and prenatal diagnostics.
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