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Parkinsonism and Other Movement Disorders Associated with Chediak-Higashi Syndrome: Case Report and Systematic Literature Review

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Authors:  Bettina Balint MD and Kailash P. Bhatia MD

Article first published online:  14 JAN 2015 | DOI: 10.1002/mdc3.12111


Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder resulting from mutations of the lysosomal trafficking regulator (LYST) gene.[1-5] Dysfunction of LYST leads to disruption of transport and fusion of lysosomes and similar organelles. This reflects in the characteristic features of (partial) albinism, if melanin is not transported to the keratinocytes; bleeding diathesis, as a result of impairment of the thrombocytic granula; and immunodeficiency, mainly because of a lack of perforin mediated cytotoxicity. The severity of symptoms varies greatly and depends on the remaining function of LYST (genotype-phenotype correlation).[6] Accordingly, the spectrum of CHS spans from childhood onset and a “mainly hematological,” potentially lethal disease course to the rarer variant of adulthood onset with slowly progressive neurodegeneration and only minor or no hematological disturbances (see Table 1). However, there is an overlap and the majority (~75%) of the cases with the later, neurological presentation do also featue immunodeficiency and/or bleeding diathesis.

Table 1. Synopsis of the different presentations of CHS

Presentations of CHS

 

 

 

 

Here, we present a case of CHS with juvenile onset of parkinsonism with video documentation of the typical features and review existing literature of movement disorder presentations of CHS. The review is based on a PubMed search for articles in English, Spanish, or German with the terms Chediak-Higashi Syndrome, neurological, parkinsonism, tremor, ataxia, dystonia, myoclonus, tics, chorea, and a combination of these. Publications were included if sufficient evidence for a diagnosis of CHS (characteristic blood smear or gene mutation) was present; enough information of neurological status was provided; and when the neurological manifestation was not a result of lymphohistocytic infiltration.

Clinical History and Examination

This patient experienced progressive gait difficulties with falls as well as cognitive decline at age 20 years. It was also noted that he had become slower and quieter.

He had a normal birth, but slightly delayed milestones, and would start walking and talking considerably later than his older brother. He displayed hyperactive behavior and went first to a nursery and later to a school for handicapped children. His past medical history comprised a meningitis at age 7 as well as recurrent otitis media, tonsillitis, and sinusitis. He would bleed excessively after minor trauma. There was no family history.

Clinical examination at the age of 32 (as seen in the Video) reveals akinetic-rigid parkinsonism with dementia, pyramidal signs, cerebellar ataxia, absent reflexes, and neuropathic foot deformities. Eye movements featured broken pursuit and slight slowing on both the horizontal and the vertical plane. There was but very mild albinism, noticeable only as a translucent iris, which became visible when testing for the pupillary reflexes.

Investigations and Treatment

Brain MRI was normal. Dopamine transporter (DaT) single-photon emission CT (SPECT) showed decreased uptake bilaterally (reported previously[7]). Blood examination showed neutropenia and a prolonged bleeding time. In the blood smear, giant, peroxidase-positive granules were detected within leucocytes. He responded very well to treatment with levodopa and dopamine agonists, but became eventually wheelchair bound and dependent in all activities of daily living during the 12 years since onset of his neurological deterioration.

Discussion and Literature Review

This patient presented with juvenile-onset parkinsonism with dementia, pyramidal signs, cerebellar ataxia, and neuropathy; he also had a past medical history suggestive of minor immunodeficiency and bleeding diathesis as well as very mild albinism.

In keeping with recent literature, this case highlights that the “red flags” of associated features—albinism, bleeding diathesis, and immunodeficiency—may be mild or even absent in patients with the adult-onset, “neurological” variant of CHS (nCHS). Hence, nCHS is perhaps underdiagnosed, and this notion is supported by recent evidence for a broadening of the phenotypic spectrum and the range of age at onset. First neurological signs usually occur in the early twenties, but age at onset is now recognized to be from the second up to the fifth decade.

A review of the existing literature of nCHS with focus on movement disorders is summarized in Table 2 and indicates that the two main presentations are that of parkinsonism, or cerebellar ataxia, mostly with additional neurological signs (see Table 2). Parkinsonism itself may be symmetric or asymmetric, akinetic-rigid, or tremulous. Interestingly, preceding nonmotor features have also been described.[8]Thus far, all reported cases had additional neurological findings, most frequently axonal neuropathy, and, to a lesser extent, pyramidal or cerebellar signs, cognitive impairment, and dystonia. Frequent oculogyric crises were reported in one patient and an upward gaze palsy in another (however, without clarification if this was indeed supranuclear).[9, 10]

Table 2. Summary of the literature reporting movement disorders in the “neurological variant” of CHS
Ref. Age of onset Sex Parkinsonism Cerebellar ataxia Neuropathy/reflex loss Pyramidal involvement Dystonia Dementia Other Hypopigmentation/partial albinism (including iris translucency) Immuno-deficiency Bleeding diathesis/thrombocytopenia
  1. All patients of references [25] and [14] underwent allogenic bone marrow transplantation for CHS.

  2. Ref., reference; nd, no data; UL, upper limbs.

[13]

31 yr

Symmetric, akinetic rigidNo response to l-dopa + + + + Learning difficulties; attention deficit + +

Fourth decade

Symmetric, tremulousl-dopa responsive + + + Attention deficit +

29 yr

Asymmetric,

tremulous

+   +
[8]

20 yr

Symmetric, mainly akinetic-rigid, impairment of postural reflexesNonmotor features: pain, fatigue, sleep disorderl-dopa responsive (+) + +   + + +
[11]

17 yr

Symmetric, akinetic rigidPostural reflex lossl-dopa responsive + + + Learning difficulties, behavioral problems + (+)
[12]

21 yr

Asymmetric, tremulousl-dopa responsive + + +   (+) +
[9]

22 yr

Symmetric, tremulousFreezing of gaitInitially l-dopa responsive + + + +

Speech difficulties; nystagmus

Oculogyric crises

+
[7, 25]

20 yr

Symmetric, akinetic-rigidl-dopa responsive + + + + Learning difficulties, hyperactive behavior + + +
[17]

19 yr

Akinetic-rigid with intermittent pill-rolling tremor postural instabilityInitially l-dopa responsive + + + Low IQ +
[10]

31 yr

Not mentioned, but patient carried a diagnosis of postencephalitic parkinsonism + + +   + +

17 yr

Not mentioned, but symmetric rest > intention tremor UL; tremor tongue, mandible + + +  

Upward gaze palsy,

CN IX palsy

+ nd nd

20 yr

Not mentioned, but

facial tremor, rest tremor UL

+ + +   + nd nd
[18]

Childhood

+ + +   Developmental delay; low IQ; epilepsy + + +

Childhood

+ + Low IQ + + +
[26]

Childhood

+ +   + + nd

Childhood

+ nd Low IQ + + nd
[15]

48 yr

+ + + +   nd nd

58 yr

+ + + +   nd nd nd
[25]

23 yr

+ + + +   + + nd
[14]

22 yr

+ + Mental retardation + + nd

20 yr

(−)

(Bilateral hand tremor, unspecified; no parkinsonism mentioned)

+ +   + + nd

24 yr

(−)

(Unspecified tremor; no parkinsonism mentioned)

+ + Myoclonus + + nd
Third decade (childhood–58 yr) ~41–63% ~81–86% ~90–95% ~59% ~14% ~41%   ~86–90% ~72–78% ~42%
 

Response to l-dopa was reported to be good in the majority of the cases, but may wear off.[8, 9, 11-13] Other drugs found beneficial were amantadine and, less so, trihexyphenidyl.[11-13] Of note, two parkinsonian patients featuring dystonia experienced a marked worsening of dystonia when treated with l-dopa, which returned to baseline when stopping the medication.[11, 12]

MRI may be normal or reveal atrophy of the brain, cerebellum, or the spinal cord.[8, 11-15] DaT-SPECT of the patient described here, showing bilaterally decreased tracer uptake, has been reported previously.[7]

Thus, nCHS adds to the differential diagnosis of young-onset parkinsonism. Oligosymptomatic nCHS may rarely mimic young-onset Parkinson's disease related to PARKIN mutations where hyperreflexia, neuropathy, and dystonia may also be present, or dopa-responsive dystonia.

More frequently, nCHS will feature a more widespread involvement and join the differential diagnosis of disorders with neuronal brain iron accumulation, Kufor Rakeb, Wilson's disease, manganese transporter deficiency, Huntington's disease, spinocerebellar ataxias (SCAs), or hereditary spastic paraplegias (HSPs), and so on. Given that some patients present with a combination of parkinsonism, pyramidal signs, cerebellar ataxia, and dystonia, it could be also considered as a differential diagnosis of MSA; however, the so far reported nCHS patients with parkinsonism were considerably younger at onset than patients with MSA and did not feature autonomic signs. Thus, nCHS could also be included in the list of autosomal-recessive ataxias or hereditary spastic paraplegias.

Other neurological manifestations include pure motor neuropathy, or neuropathy with pyramidal signs; sensorineuronal deafness; epilepsy, or cranial nerve palsies.[16-20] Mental retardation, developmental delay, or behavioral disturbances in early childhood can be part of the picture.[13, 14, 20, 21] Ocular albinism itself may manifest as congenital nystagmus, photophobia, reduced visual acuity, color vision impairment, and progressive vision loss.[9, 10, 13, 22, 23]

Of note, the blood smear of patients with nCHS is diagnostic and will demonstrate peroxidase-positive giant granules within leukocytes; it is cheaper and more feasible than genetic testing in many places and allows easy screening whenever nCHS is considered. Unfortunately, there is no curative treatment for nCHS to date, and management remains symptomatic.

In conclusion, clinicians should be considering nCHS in anyone with young-onset parkinsonism and should look out for tell-tale features such as albinism, bleeding diathesis, or frequent infections.

Even though the exact pathomechanisms remain elusive, impairment of lysosomal trafficking is what nCHS shares with some other genetic causes of parkinsonism, for example, mutations in ATP13A2, LRRK2, SNCA (α-synuclein), or GBA (glucocerebrosidase).[24]

 

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