Atypical Chédiak-Higashi syndrome with attenuated phenotype: three adult siblings homozygous for a novel LYST deletion and with neurodegenerative disease

Mutations in LYST result in Chédiak-Higashi syndrome (CHS; MIM 214500), a rare autosomal recessive disorder typically characterized by immune dysfunction in early childhood, partial oculocutaneous albinism and other pigmentary abnormalities, and, in survivors of the accelerated phase of immune deterioration, late-onset neurologic dysfunction. Progressive neurodegenerative disease with subtle pigmentary abnormalities and absent or subclinical immunologic abnormalities are the hallmarks of the attenuated form of CHS [1–3]. This form of CHS has been estimated to account for 10–15% of all CHS patients [4], but may be underdiagnosed. Neurologic manifestations appear to be variable, but frequently include peripheral neuropathy, intellectual decline, parkinsonism, ataxia, and white matter abnormalities [4–8]. Genotyping of individuals with these phenotypes has, to date, identified only four causative LYST genotypes, all of them missense mutations; infantile-onset disease is associated with null LYST alleles. Here we report a large consanguineous family with three adult siblings each homozygous for a novel deletion in exon 43 of LYST and with variable pigmentary abnormalities and adult-onset neurodegenerative disease.

We present three adult siblings as examples of a rare, attenuated form of Chédiak-Higashi syndrome, manifesting with progressive neurodegenerative disease and with mild or subclinical immunologic abnormalities, and abnormal pigmentation. Neurologic manifestations in this form of CHS are variable, but frequently include peripheral neuropathy, cognitive decline, and features of spinocerebellar degeneration with cerebral and cerebellar volume loss and abnormal white matter appearances on MRI [4, 7, 8]. Dystonia has also been reported [9]. HLA-identical allogeneic bone marrow transplant (BMT) was reported as an acceptable curative treatment for classic CHS almost 20 years ago [10]. Despite demonstrating efficacy in treating the immunodeficiency component of the disease, similar neurodegenerative features have also been observed at a similar age in BMT recipients with classical CHS phenotypes [11, 12]. Our patients had learning difficulties, attention-deficit behaviors and other neuropsychologic deficits that may have significantly predated the onset of frank neurologic symptoms. Classical CHS has also been associated with learning difficulties in young children, and, later, with progressive, diffuse white matter abnormalities on MRI as well as neurologic decline and accelerated immune deterioration [4, 13, 14].

LYST is a ubiquitously expressed gene whose protein product is concerned with control of exocytosis and trafficking from secretory lysosomes [3, 5, 15, 16] and may be critical to microtubular stability. Several distinct domains within the LYST polypeptide appear to be critical to protein-protein interactions and organization of protein complexes important to lysosome-related organelles [17]. Cytoplasmic giant granules, seen in leucocytes, are a hallmark of CHS, and are also seen in neuronal cells and perineuronal tissue [3]. Enlargements of lysosome-derived organelles are also characteristically observed [18]. Consistent with our experience, other authors [8, 19] have reported that granules in patients with attenuated disease are enlarged, but not as dramatically as is seen in classic forms of the disease; it is therefore conceivable that the diagnosis may be missed by inexperienced technologists. With regard to observed neurologic deterioration with advancing age, clumped irregular melanin granules have been observed in the substantia nigra in human patients at autopsy [20, 21]. Murine models of CHS with homozygous missense mutations in LYST have exhibited predominant neurologic phenotypes including lower motor performance scores than controls, with accumulation of giant lysosomes in neuronal cells and intracytoplasmic inclusions in Purkinje cells of the cerebellum and motor cortex [22]. At autopsy, adults with CHS had neuronal degeneration involving the inferior olivary nuclei and the cerebellar cortex, with an overall distribution similar to late cortical cerebellar atrophy (LCCA) and olivopontocerebellar atrophy (OPCA), but without pontine involvement [20].

AA protein (reactive) amyloidosis is usually observed in the setting of chronic infectious or inflammatory disease. Systemic AA amyloidosis has been reported previously in the setting of CHS, both in humans [20] and in animals [18]. The only previous human report described a Japanese woman with classic CHS who suffered recurrent pyogenic infections and albinism noted from infancy, and had post-mortem evidence of amyloid deposition in multiple tissues including the kidney, liver, thyroid, and ovary, and pituitary and parotid glands. Reactive gliosis was observed in the brain. The authors speculated that recurrent infections had contributed to the development of amyloidosis, and that amyloid deposition would become an increasingly common observation in CHS patients with classic phenotypes as a function of cumulative burden of recurrent, severe infection, especially as these patients survive into adolescence and adulthood in greater numbers as is anticipated as BMT protocols become more refined with improved efficacy and reduced toxicity [20]. Neutropenia, observed chronically or intermittently, has been reported in CHS [23], and the fact that our patients were not neutropenic at the time of evaluation does not exclude historical episodes of neutropenia. However, in view of the fact that our patients do not have any significant history of recurrent infection, but have skin biopsy appearances consistent with amyloid deposition, we suggest that amyloidosis may be a component of the pathophysiology of CHS that is independent of the burden of recurrent infection.

It has been suggested that neurologic manifestations result directly from defective LYST in neurons and glial cells, or from lymphocytic tissue infiltration during the accelerated phase of the disease. Acute CNS manifestations, as well as the presence of long-term neurologic defects, are described in other inherited hemophagocytic disorders (Griscelli syndrome, X-linked lymphoproliferative disease). Each of these disorders is amenable to BMT [24], but neurologic disease develops despite successful BMT. Like CHS, Griscelli syndrome type 2 can cause pigmentary abnormalities with hair graying, as well as neurological disease, and is an important differential diagnosis in this setting. Expanding knowledge of the role of lymphocytic CNS infiltration in causing neurodegenerative disease in CHS may determine optimal timing of transplant in CHS patients, given the fact that many patients, if not all, appear destined to develop debilitating neurodegenerative disease over the longer term. In the United States, transplant if routinely offered in advance of the accelerated phase of classic disease. In a single-center review of the use of hematopoietic stem cell transplantation (HSCT) in Griscelli syndrome type 2 [25], many patients continued to suffer major neurological deficits after HSCT, leading the authors to suggest that transplanting these patients prior to the accelerated phase could be beneficial. The presence of neurodegenerative signs appearing in classical CHS patients many years after BMT suggests that neurodegeneration may be related in part to defective lysosomal trafficking and vacuolar dysfunction. More recently, it has been shown in a murine model that various pathophysiologic aspects of CHS might be directly dependent on oxidative membrane damage [17]. Due to the large size of neurons and their expansive plasma membranes, these and other cell types may be especially sensitive to the adverse effects of accumulation of oxidatively damaged cell membranes.

The in-frame nature of the novel LYST deletion, present in the homozygous state in all of the affected siblings in this family, may account for the comparatively mild, late-onset phenotype in these individuals. The deletion is located distally in LYST (exon 43 out of 51), and causes loss of two amino acid residues in the BEACH domain of LYST, but does not cause a frameshift/premature termination. To our knowledge, only four other mutations, all missense, have been definitively associated with attenuated phenotypes. A previously reported patient with classic CHS [12] was a compound heterozygote for single base pair deletion (c.9893delT) in a similar region of the BEACH domain and a more proximal nonsense mutation (c.1540C>T). The deletion caused a frameshift resulting in premature protein truncation downstream (F3298fsX3304), and resulted in an infantile-onset immunodeficiency and lymphoproliferative histiocytosis phenotype. Homozygosity for the mutant allele in our cases suggests the siblings’ parents share a common ancestor. Parents denied being directly related, although both families originate from the same region of Pakistan. CHS has not, to our knowledge, been previously reported in Pakistani kindreds.

Based on our experiences, and the available literature [8, 9, 26], patients with this pattern of CHS might benefit, at least in the short term, from L-dopa, selegiline, trihexylphenidyl, biperiden, or amantadine. At diagnosis, patients require multidisciplinary input from a neurologist with expertise in movement disorders, as well as a clinical immunologist (even if historical clues suggesting immunodeficiency are absent), an ophthalmologist, a neurophysiologist, and a neuroradiologist. Both affected brothers in this family had below normal levels of testosterone but had fathered children; the significance of this finding is unclear and requires further study.

This family expands the phenotype of CHS, and provides additional characterization of central nervous system disease in such patients. These patients have complex medical needs and require carefully integrated multidisciplinary care. The pathophysiology of this form of the condition is likely to be related to a combination of factors including microtubular instability, impaired lysosomal trafficking, oxidative injury, and amyloid deposition. Variant CHS is phenotypically heterogenous and should be considered when young adults develop neurodegenerative disease in association with pigmentary abnormalities. The disorder can be easily screened for with characteristic findings on peripheral blood smear and hair sampling, although these may be less conspicuous than in classic CHS phenotypes.