Huntington's disease-like syndrome

Overview

Huntington's disease-like syndrome (HD-like syndrome) refers to a group of rare neurodegenerative disorders that clinically resemble Huntington's disease but are caused by different genetic mutations. Patients present with symptoms such as chorea (involuntary movements), cognitive decline, and psychiatric disturbances, similar to those seen in classic Huntington's disease (HD). These conditions are collectively termed "HD-like" because they mimic HD in presentation but are not caused by the HTT gene mutation responsible for Huntington’s disease.

Causes

While classic Huntington’s disease is caused by a CAG trinucleotide repeat expansion in the HTT gene, HD-like syndromes arise from mutations in other unrelated genes. Some recognized types include:

• HDL1: Caused by a prion protein gene (PRNP) mutation

• HDL2: Most common in individuals of African descent; caused by mutations in the JPH3 gene

• HDL3: Very rare and genetically unresolved; believed to be autosomal recessive

• Other disorders such as neuroferritinopathy, dentatorubral-pallidoluysian atrophy (DRPLA), and spinocerebellar ataxias (SCAs) may also present as HD-like conditions

These syndromes are usually inherited and result from different mechanisms affecting neurons in the basal ganglia and cerebral cortex.

Symptoms

The symptoms of Huntington’s disease-like syndromes closely mirror those of classic HD and typically include:

• Chorea (involuntary, jerky movements)

• Dystonia and muscle rigidity

• Progressive cognitive decline and memory issues

• Personality changes, depression, anxiety, or psychosis

• Speech and swallowing difficulties

• Loss of coordination and balance

Age of onset, progression, and symptom severity can vary depending on the specific HD-like condition and genetic cause.

Diagnosis

Diagnosis of HD-like syndrome is considered when a patient presents with Huntington's disease symptoms but tests negative for the HTT gene mutation. The diagnostic workup includes:

• Detailed neurological and psychiatric examination

• Family history assessment

• Genetic testing for HTT gene to rule out classic HD

• Further genetic testing for PRNP, JPH3, DRPLA, or other relevant genes

• Brain imaging (MRI or CT scan) to identify structural brain changes

Accurate diagnosis requires collaboration between neurologists, geneticists, and neuropsychologists.

Treatment

There is currently no cure for HD-like syndromes. Treatment focuses on managing symptoms and improving quality of life. Options may include:

• Medications: Antipsychotics (e.g., haloperidol), tetrabenazine, and antidepressants to manage chorea and psychiatric symptoms

• Physical therapy: To help maintain mobility and reduce falls

• Speech and occupational therapy: To assist with communication and daily functioning

• Psychological support: For patients and families dealing with cognitive and emotional challenges

In advanced stages, supportive care and palliative measures may be needed.

Prognosis

The prognosis for Huntington’s disease-like syndromes varies depending on the specific subtype and severity of symptoms. Most forms are progressive and eventually lead to significant neurological disability and reduced life expectancy. The rate of progression and response to treatment also vary. Early diagnosis and multidisciplinary care can help improve symptom management and quality of life, but long-term outcomes remain guarded.