Adult‐onset Neuronal Ceroid Lipofuscinosis (Kufs Disease) with Autosomal Dominant Inheritance in Alabama (2003)

The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous group of hereditary neurodegenerative disorders in which progressive tonic–clonic and myoclonic seizures as well as progressive cognitive decline are associated with abnormal lipopigments from lysosomal inclusion bodies in neurons and other cells (1). The rarest of the four types of NCLs is the adult type, Kufs disease. All four types demonstrate accumulation of autofluorescent pigment within brain, myenteric plexus, muscle, and skin. Ultrastructurally granular osmiophilic deposits (GRODs) or fingerprint, and rectilinear, or curvilinear profiles are present (2,3). In Kufs disease, fingerprint and rectilinear profiles and GRODs have been reported (4,5). New diagnostic techniques allow identification of several of the NCLs, but Kufs disease still remains rare and poorly characterized. The clinical characteristics, in which there is lack of pigmentary retinal degeneration, and the neuropathologic investigation, permit its identification (6,7). Two clinical types of Kufs disease have been described: type A, in which generalized tonic–clonic seizures develop by age 30 years, followed by myoclonic epilepsy, ataxia, and dysarthria; and type B, in which behavioral disturbances and dementia predominate (8,9). The NCLs are inherited in autosomal recessive fashion, except for five families with dominantly inherited Kufs disease (4,5,9,12). We report an additional family with autosomal dominant inheritance, the first one originally from Alabama, in which at least four generations have been affected (Fig. 1). We report the neuropathologic findings from one autopsy and biopsies from others, as well as the clinical presentation and course. Family tree of the affected patients. Open symbols, nonaffected cases; closed symbols, affected cases; grey symbols, patients with only history of seizures. Diagonal marks are deceased patients. The index case (F-4 in Fig. 1) was self-referred to our center when he was 30 years old because of progressive myoclonus, dysarthria, and ataxia. Members of his family had been evaluated previously at UABEC (E1, E3, E4, E5, and E6). The family is from rural northwest Alabama. They are unaware of the family's origin before migration to Alabama, and unaware of kinship with previously reported families with Kufs disease. No history of consanguinity exists. The evaluations consisted of complete neurologic examinations, cerebrospinal fluid examination in three patients, neuroimaging studies in four, interictal EEG in three members of the family, and prolonged video-EEG monitoring in the index case and two others. A complete neuropathologic examination was made of case E3, including routine light, fluorescent, and electron microscopy. The clinical features of the family are summarized in Table 1. On neurologic examination, this 30-year-old right-handed man had a mini-mental status examination (MMSE) of 29 out of 30, mild dysarthria, with low-volume and monotonal speech, mild tremor of the hands, and occasional myoclonic jerks of the left hand. The EEG examination revealed a slow background with generalized polyspikes and polymorphic delta slowing, most prominent in the frontal regions. Initial treatment consisted of valproic acid (VPA). One year later, he had an MMSE score of 25 of 30, with more prominent myoclonic jerks and ataxia. He reported having episodes of falling with diverse injuries. In the interim, he had an episode of generalized tonic–clonic seizures and was given phenytoin (PHT) in a local emergency room. He was admitted to the UAB epilepsy unit for intensive monitoring and change in medication regimen. In the hospital, his interictal EEG had a slow background with frequent generalized polyphasic spike and slow-wave discharges, and spike and slow-wave discharges in both frontal regions. During low-frequency photic stimulation, myoclonic jerks were elicited (photomyoclonic response). Ictal recordings captured myoclonic jerks simultaneous with generalized polyspike and wave activity, sometimes followed by 1–2 s of attenuation of the background (Fig. 2). Zonisamide (ZNS) was introduced to a target dose of 300 mg/day. He improved and, on examination 2 months later, had minimal dysarthria, only slight myoclonic jerks, and was able to walk independently. Ictal recordings captured myoclonic jerks simultaneous with generalized polyspike and wave activity, followed by 1–2 s of attenuation of the background. EEG in bipolar montage. Four other family members were evaluated at the UABEC, both clinically and with muscle and skin biopsies. The parents and grandparents of these four patients were not examined. However, family members described myoclonus, dementia, and tonic–clonic generalized seizures in all of them. The family members with symptoms to date have inherited the disease from their mothers (Fig. 1). Several of the patients' relatives have had seizures without any other known symptoms. Patients in generation C had only tonic–clonic generalized seizures and died in their 80s. A cousin of our index case has febrile seizures, and his sister has a male child, who apparently is asymptomatic. Not included in Fig. 1 are nine children of the affected male in generation C, all without neurologic disease, and 21 grandchildren, two of whom have seizures only. The clinical findings in our patients are quite similar (Table 1). The initial symptom in all was a tonic–clonic seizure occurring between the ages 27 and 29 years. Progressive tonic–clonic and myoclonic seizures, dementia, and parkinsonism developed over the subsequent 2–5 years. Two saw flashing lights as an aura to their seizures. Two had atonic seizures. Three patients were placed in nursing homes in their mid-30s, and death occurred by inanition in the five patients in generation E between ages 46 and 49 years. On physical examination, all four patients (E3, 4, 5, and 6) were alert and oriented but demonstrated deficits in attention, recent memory, and abstract thinking. Their speech was low in volume, had a monotonous quality, and was dysprosodic. Facial expressions were hypomimic. Motor strength and tone were normal; there was no cogwheel rigidity. However, they walked with a slight stoop, and their stride length was reduced. Postural reflexes were affected, and some falls occurred. Cerebellar functions were normal. A fine hand tremor, which increased with higher VPA levels, was present in all. Voluntary movements were frequently interrupted by multifocal myoclonic jerks, which also were present with lesser amplitude at rest. Reflexes were hyperactive, and two of them had a Babinski sign. None of them had hypertension, optic atrophy, retinal degeneration, or cherry-red spots on fundoscopic examination. One of the authors (E.F.) traveled to Virginia to examine patient E1 at her age 47 years. She was stuporous and bed-bound, having had a severe head injury from a fall 2 years earlier. Examination of her medical records revealed a clinical course similar to those of her half-siblings. Their seizures progressively worsened despite aggressive treatment with antiepileptic medications (AEDs). VPA and clonazepam (CZP) were used. PHT was beneficial in the early stages when only tonic–clonic seizures were present, but seemed to worsen the myoclonus once it was manifested. CSF examination performed on three of our patients was normal. Computed tomography (CT) scan of the head was performed on three patients: two were normal, and one showed mild atrophy. Magnetic resonance imaging (MRI) was performed in one patient and was normal. EEGs were abnormal in all patients, showing generalized and multifocal spikes and polyspikes. No abnormal responses to photic stimulation were found. Urinary sediment dolichols were measured in the urine of two male patients: one had 0.6 μg/mg lipid, 2.2 μg/dl, and 23.5 μg/g creatinine, and the other had 6.3 μg/mg lipid, 1.5 μg/dl, and 12.9 μg/g creatinine. These values were not clearly abnormal. Wright's stains of peripheral blood smears showed no evidence of neutrophilic hypergranulation or lymphocytic vacuolization. Routine light microscopy of skin and muscle biopsies was unremarkable in all patients. However, fluorescent microscopy of frozen sections of muscle and skin were abnormal in all specimens. Pale yellow autofluorescent pigment was present within muscle fibers and particularly eccrine glands. Electron microscopy (EM) of eccrine glands and muscle revealed GRODs in all of our four patients. GRODs also were identified in the brain biopsy of one of the patients (Fig. 3). These GRODs were uniform in size and occupied a significant portion of the cytoplasm of most cells. They were clearly present within muscle, but not so abundantly as in eccrine cells, and were numerous in the brain. Some GRODs were associated with lipid vacuoles. The morphology of the GRODs was similar in all patients examined. Fingerprint, rectilinear, or curvilinear profiles were not present. Ultrastructural examination from a brain biopsy in one patient demonstrates GRODs (granular osmiophilic deposits) (×18,900). The neuropathology from the autopsy of case E3 was reviewed. Grossly, mild symmetric cerebral and cerebellar atrophy was present. On routine H&E staining of paraffin-embedded material, marked accumulation of brownish pigment was observed within nearly all of the cortical, basal ganglia, brainstem, and spinal cord neurons. This pigment was located in the neuronal perikarya, and was periodic acid–Schiff positive (Fig. 4). Ultrastructural examination demonstrated GRODs in the cells with storage product. Marked chronic astrogliosis also was found. Rare substantia nigra neuronal loss and pigmentary incontinence was seen. Sections of the right hippocampus demonstrated significant neuronal storage in Ammon's horn, the CA4 region, and in the neurons of the fascia dentata. No tangles or plaques were identified. At autopsy, neocortical neurons are distended with periodic acid–Schiff (PAS)-positive storage material (PAS, ×210). NCLs are rare (two to four per 100,000 live births) (10). They are classified as infantile (CLN1; Santavuori–Haltia disease), classic late infantile (CLN2; Jansky–Bielschowsky disease), juvenile (CLN3; Batten disease or Spielmeyer–Vogt–Sjögren disease), and adult-onset (CLN4; Kufs disease) forms. Two variants of the late infantile NCL have been designed as CLN5 and CLN6 (10). Kufs disease represents ∼1.3% of the NCLs (11). Our patients' family tree shows an apparent autosomal dominant inheritance (Fig. 1), because the disease is present in each generation, but all family members with the full-blown syndrome inherited the disease from their mothers. In 1971 Boehme et al. (4) reported a New Jersey family with autosomal dominant Kufs disease. The clinical and pathologic characteristics of their family are remarkably similar to those of ours. As in our family, their six patients had generalized tonic–clonic seizures. The age at onset in their family was slightly older than in our family, between ages 30 and 32 years in five of their patients and at age 40 years in one. All of their patients had myoclonus and abnormal speech. Their four oldest patients became demented. The main differentiating factors are the presence of cerebellar dysfunction, essential hypertension, and neutrophilic hypergranulation in their family, and the presence of parkinsonism in our family. Of their six patients, five had incoordination, five had essential hypertension, three had neutrophilic hypergranulation, and none had parkinsonism. Ultrastructurally their family had GRODs within cortical neurons. Our family has GRODs within muscle, eccrine glands, and brain tissue. Ferrer et al. (5) described another family with autosomal dominant Kufs disease in 1980. The age at onset was between ages 33 and 37 years. The presenting complaint in five of six patients was mental impairment. The other patient had generalized tonic–clonic seizures at age 32 years. All patients subsequently developed dystonic involuntary movements of the face and neck. Myoclonus was not described in these patients. Cortical neurons showed accumulations of brown–yellow, autofluorescent material. Ultrastructurally rectilinear profiles were present. Arpa et al. (12) presented two families at the 1978 meeting of the Spanish Neurologic Society as having autosomal dominant ceroid lipofuscinosis with prominent cerebellar dysfunction. However, only light microscopy was performed, and the pathologic findings were poorly documented. A recent article by Josephson et al. (9) reports a family from Missouri in which 10 members were affected. The onset was in the fourth decade of life and was heralded by seizures, and the features resembled those of the families previously described as well as ours. The clinical course was dominated by seizures and myoclonus (type A), as well as dementia and extrapyramidal findings (type B). Elevated urinary sediment dolichols have been reported in the NCLs (13), but we do not feel that our patients' lack of abnormal urinary dolichols casts doubt on the diagnosis because the false-negative rate for urinary sediment dolichol determination is between 7.5 and 15% in infantile and juvenile cases of NCLs (8). Genetic evaluation can be helpful in the diagnosis of some of the NCLs, the infantile (CLN1, gene at 1p32), the classic-late infantile (LINCL or CLN2, gene at 11p15), and the juvenile form (CLN3, gene at 16p12). Even variants of the late-infantile NCL have genotypic correlations (Finnish variant or CLN5, gene at 13q22; the Gypsy/Indian variant or CLN6, gene at 15q21; and the Northern Epilepsy or CLN8, gene at 8p23), but for adult NCL (CLN4), the gene has not been identified (14). To date, CNL7 appears to be allelic to CLN8 (15,16). The infantile form of NCL may have an adult onset, especially when only GRODs are present at the EM level, and this may be caused by a deficiency of palmitoyl-protein thioesterase, and for that reason, screening and enzyme analysis should always precede gene analysis looking for mutations in CLN1, in new cases (17). Pathologic findings in our patients are consistent with the diagnosis of Kufs disease, including the neuronal accumulation of lysosomal storage material in the form of GRODs, which were present in the brain and skin. Usually Kufs disease is associated with mixed type of inclusions (GRODs, curvilinear and fingerprint profiles). The usefulness of VPA and CZP in certain stages of the disease was not surprising. In a group of 26 patients with progressive myoclonic epilepsy, it was found that the combination of VPA, CZP, and phenobarbital (PB) was particularly beneficial (18). Use of ZNS in this condition requires further research, but has been useful in patients with other forms of progressive myoclonic epilepsy (19). The differential diagnosis for progressive myoclonic epilepsy beginning in the late 20s or early 30s is quite small. It includes the mitochondrial encephalomyopathies, sialidosis type II, dentatorubro-pallidoluysian atrophy, and atypical inclusion-body disease (7,8). The possible maternal inheritance in our family would suggest a mitochondrial encephalomyopathy. However, in these conditions, one would expect ragged red fibers within muscle, elevated CSF protein, external ophthalmoplegia, short stature, and hearing loss. These features were not present in our patients. In sialidosis type II, one would expect cherry-red spots and dysmorphic features. Dentatorubro-pallidoluysian atrophy is ruled out by the absence of choreoathetosis and dystonia. In Lafora disease and atypical inclusion-body disease, Lafora bodies or Lafora-like bodies are present. This is the sixth published report of a family with well-documented, autosomal dominant Kufs disease. The clinical diagnosis was confirmed by skin and muscle biopsies. Eccrine glands and skeletal muscle contained autofluorescent pigment by fluorescent microscopy and GRODs by EM. Our family is the second reported family with autosomal dominant Kufs disease in which the pathologic diagnosis was made in extracerebral tissue, even though the sensitivity and specificity of these findings in the diagnosis of Kufs disease is not well known. It is the second family with Kufs disease (recessive or dominant) reported in the medical literature in which parkinsonism has been described (20). Further research is needed to elucidate the genes and proteins involved in the etiology of this type of adult-onset neuronal ceroid lipofuscinosis.