This article describes other possible diagnoses when there are clinical signs of HD but a negative gene test.
We have been contacted from time to time by families with a loved one who has been clinically diagnosed with Huntington's Disease but who has tested negative. In each case, no one in the family had previously tested positive for the Huntington's Disease gene. The families were interested in getting a list of other possible diseases with HD symptoms. Some of the Huntington's Disease-Like Syndromes are so rare that the patient's doctor may be unaware of them.
The authors of this study have produced a helpful article for physicians and families faced with the challenge of diagnosis under these circumstances.
Here are some other genetic disorders with symptoms like those of Huntington's Disease:
HDL-1 (for Huntington's Like-1) is caused by a mutation in the prion protein gene. It is an automsomal (not on an X or Y chromosome) dominant genetic disorder with similar symptoms to HD. It causes atrophy to the basal ganglia (like HD) as well as to the frontal and temporal lobes and the cerebellum. The mean age of onset is somewhere between 20 and 45 years of age.
HDL-2 is caused by an expansion of CTG and CAG repeats in the junctophilin gene. The symptoms are very similar to HD and the brain pathology is somewhat similar. The mean age of onset is between 30 and 50 but there is a juvenile form of the disease. With the exception of one Brazilian family, the disease has only been found in families of African origin.
HDL-3 turned up in Saudi Arabia. It is an autosomal recessive disorder which strikes in early childhood with symptoms resembling those of juvenile Huntington's Disease. The problem gene has not been conclusively identified.
HDL-4 is caused by an expansion of CAA and CAG repeats in the TBP gene. It is also called spinocerebellar ataxia 17. The symptoms of this disease vary but it can present with HD symptoms. Patterns of brain atrophy also vary.
Dentatorubal pallidoluysian atrophy (DRPLA) is caused by an expansion of CAG repeats on the atrophin 1 gene. Symptoms can vary but the disease can present like HD. The average age of onset is between 20 and 30 but it can occur in childhood. It is more likely to be found among those of Japanese ancestry but has occasionally been found in other ethnic groups.
Neuroferritinopathy is an autosomal dominate disorder caused by a mutation in the ferritin light chain gene. It causes chorea, dystonia, and Parkinsonian symptoms.
Wilson's disease is an autosomal recessive disorder caused by a mutation of the gene ATP7B which results in the brain and body accumulating excess copper. Symptoms usually start between 10 and 21 but can start as late as age 50. They include slurred speech, difficulty swallowing, and dystonia. About a third of Wilson's disease patients have psychiatric problems.
Note: There are treatments for neuroferritinopathy and Wilson's Disease, so it is especially important that these diseases be correctly diagnosed when present!
Chorea acanthocytosis is an autosomal recessive genetic disorder caused by a mutation in the vacuolar protein sorting 13 homolog A gene. The pattern of brain damage is similar to HD. Onset occurs in young adulthood. Symptoms include chorea, dystonia, Parkinsonian symptoms, seizures, subcortical dementia, peripheral neuropathy, tics and eye movement abnormalities. A possible psychiatric symptom is self-mutilation.
McLeod syndrome is a recessive genetic disorder which is caused by a mutated XK gene on the X chromosome. It is also an acanthocytosis disorder. Symptoms include chorea, dystonia, Parkinsonian symptoms, seizures, psychiatric peripheral neuropathy.
Pantothenate-kinase-associated-neurodegeneration (PKAN) is a recessive genetic disorder which is caused by mutations on the PKAN2 gene or the PLA2G6 gene in which causes the excessive accumulation of iron. PKAN is also referred to as Hallervorden-Spatz syndrome or neurodegeneration with brain iron type 1 (NBIA1). Onset occurs in childhood. Symptoms vary but can include dystonia, chorea, dementia, Parkinsonian symptoms, slurred speech and difficulty swallowing.
If a family member lacks a diagnosis for HD like symptoms, e-mail me and I will send you whatever information I can find. Families dealing with a rare HD like disorder are very welcome in the online HD community.
Huntington's disease (HD), which is caused by a triplet-repeat expansion in the IT15 gene (also known as huntingtin or HD), accounts for about 90% of cases of chorea of genetic etiology. In recent years, several other distinct genetic disorders have been identified that can present with a clinical picture indistinguishable from that of HD. These disorders are termed Huntington's disease-like (HDL) syndromes. So far, four such conditions have been recognized, namely disorders attributable to mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), and the gene encoding the TATA box-binding protein (HDL4/SCA17), and a recessively inherited HD phenocopy in a single family (HDL3), the genetic basis of which is currently poorly understood. These disorders, however, account for only a small proportion of cases with the HD phenotype but a negative genetic test for HD, and the list of HDL genes and conditions is set to grow. In this article, we review the most important HD phenocopy disorders identified to date and discuss the clinical clues that guide further investigation. We will concentrate on the four so-called HDL syndromes mentioned above, as well as other genetic disorders such as dentatorubral-pallidoluysian atrophy, neuroferritinopathy, pantothenate-kinase-associated neurodegeneration and chorea-acanthocytosis.