Neurology: Case of the Month

Check Your Diagnosis — Patient 71

Shari Rosen-Schmidt, M.D.

Diagnosis

Neuronal Ceroid Lipofuscinosis

Clinical Summary

This patient presented with childhood onset of developmental delay followed by psychomotor regression, seizures, and optic atrophy. Organomegaly was not evident on examination, nor was there a clear family history. MR imaging demonstrated diffuse cortical atrophy. The differential diagnosis for an early childhood-onset neurodegeneration involving visual and cortical systems would include the GM1 and GM2 ganglioside storage disorders, Niemann-Pick disease (type C), neuronal ceroid lipofuscinoses, and less likely a variant of Gaucher disease or of metachromatic leukodystrophy. We found that assays for the enzymes beta-glucosidase, hexosaminidase A and B, and sphingomyelinase were normal. Fluorescence microscopy and electron microscopy of the leukocyte "buffy coat" of peripheral blood was mildly abnormal, but not diagnostic. Conjunctival biopsy demonstrated curvilinear and finger-print bodies in endothelial cells, supporting a diagnosis of neuronal ceroid lipofuscinosis. Molecular genetic data on this patient are not available at this time.

Discussion

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited, severe neurodegenerative disorders manifested pathologically by accumulation of autofluorescent lipopigments, ceroid and lipofuscin, in lysosomes in tissues of the CNS and to a lesser extent in peripheral tissues. Clinically, these disorders are characterized by progressive visual loss leading to blindness, seizures, and psychomotor deterioration. Some of these disorders also have polymyoclonus or myoclonus as major manifestations. The overall frequency of NCL is about 1.2 per 100,000 live births, making them the most common of the lysosomal storage diseases. However, in certain regions such as Finland, the frequency of the infantile form can be as high as 7.7 per 100,000 live births. All of the disorders are inherited in an autosomal recessive pattern, except for a rare adult-onset form that is autosomal dominant. Classically, the disease has been divided into four major groups based on the age of onset of symptoms, the histopathology of the storage material by electron microscopy (granular osmiophilic deposits, curvilinear, or fingerprint profiles, or mixed patterns), and the clinical course. The four prototypical classifications are the infantile, late infantile, juvenile, and adult forms of NCL. In the latter three forms of NCL, subunit C of mitochondrial ATP synthase accumulates to varying degrees in lysosomes (Lake and Hall 1993), whereas sphingolipid activator proteins accumulate predominantly in the infantile subtype. Each of the four prototypical groups has been labeled with an eponym. Batten's Disease is often used to collectively refer to the NCLs; however, this eponym also is used to refer to juvenile NCL, being a contraction of the eponym Spielmeyer-Vogt-Sjogren-Batten disease (Bennett and Hofmann 1999). At least eight subtypes, taking into account genetic features, have been proposed in the NCLs (NCL1-8).

Infantile Neuronal Ceroid Lipofuscinosis (INCL)

INCL, or Haltia-Santavouri disease, has the earliest age of onset and is the most severe of the classic four NCL subtypes. In this disorder, seizures usually begin in the first year, followed by loss of developmental milestones, ataxia, hypotonia, and blindness caused by retinal degeneration and optic atrophy. Death usually occurs by age 10.

The electroretinogram amplitude in patients with INCL is quite diminished or even absent very early in the disease. The visual evoked response diminishes and disappears with age. Deposits seen with electron microscopy are the granular osmiophilic type in lymphocytes and can be seen in skin, muscle, and conjunctiva biopsies. Diffuse brain atrophy can be seen by MRI as well as post-mortem. EEG may show flattening by 18-24 months, and may be isoelectric by 3-4 years (Goebel 1994). Linkage studies suggested localization of INCL (CLN1 subtype in the new classification) to chromosome 1p32, followed by the identification of palmitoyl-protein thioesterase (PPT) as the defective enzyme in this disease (Vesa et al 1995). PPT is the enzyme that hydrolyses the palmitate thioesters of fatty-acylated cysteine residues in proteins (Camp et al 1994).

Late Infantile Neuronal Ceroid Lipofuscinosis (LINCL)

LINCL, or Bielschowsky-Jansky disease, typically has an onset between 2-4 years of age, although some authors allow for later onset, up to 8 years. Seizures are most often of mixed types, with both generalized tonic-clonic and partial motor seizures occurring prior to age 4. Truncal ataxia, hypotonia, and dysarthria with progressive spasticity then follow. Myoclonus can also occur. Visual loss usually develops within two years of initial symptoms and death typically occurs within 10 years after onset.

The electroretinogram is quite diminished or absent as in INCL; however, unlike INCL, the visual evoked response is actually increased prior to a gradual reduction over time. Photic stimulation produces characteristic high amplitude, polyphasic discharges that can be seen with EEG. MRI initially shows cerebellar atrophy, but as the disease progresses, there can be diffuse atrophy (Boustany 1993). Deposits seen by electron microscopy are most often curvilinear, but can have mixed features. LINCL (CLN2 in the new classification) has been mapped to 11p15, (Sharp et al 1997). The CLN2 gene in affected individuals was found to be a pepstatin-insensitive lysosomal protease, homologous to tripeptidyl peptidase I, and mutations in this gene were found to cause deficiency in this peptidase (Sleat et al 1999). Other variants of LINCL also occur, assigned to subtypes NCL 5-7. A Finnish variant maps to a locus designated CLN5 on 13q22; an Indian-Costa Rican variant maps to CLN6 on 15q21-23; and the locus for a Turkish variant is designated CLN7 (Dawson and Cho 2000).

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL)

Juvenile NCL (Spielmeyer-Vogt-Sjogren-Batten disease, also called Batten disease) may account for a high proportion of all cases of NCL. Clinically, vision loss is associated with retinitis pigmentosa, and usually occurs between ages 4 to 10. Generalized tonic-clonic and myoclonic seizures begin in mid-childhood, but are not as difficult to treat as seizures occurring in the other childhood forms of NCL. The cortical symptoms are milder than with INCL and LINCL, and initially may only be noticed by decreased academic performance and personality change.

In patients with JNCL there is no photoconvulsive response and the electroretinogram is usually diminished. The characteristic deposits seen with electron microscopy are mainly fingerprint bodies. The gene is designated NCL3, mapped to chromosome 16p12, and codes for a transmembrane protein of unclear function (Bennet and Hofmann, 1999).

Adult-Onset Neuronal Ceroid Lipofuscinosis (ANCL)

Adult-onset NCL (Kuf's disease) is the rarest form of NCL, accounting for only 2% of all NCL cases. Onset of symptoms is usually in the second to third decade. There is no visual loss in ANCL. Unlike all the other strictly autosomal recessive forms of NCL, in ANCL there is a small percentage of cases that are inherited as an autosomal dominant disease. ANCL is a clinically heterogeneous disorder with slow deterioration and spasticity. Some sources divide ANCL into two types: Type A with seizures and myoclonus and Type B with some combination of dementia, progressive ataxia, spasticity, rigidity, and choreoathetosis. Psychosis has also been reported.

In ANCL the somatosensory evoked potentials as well as visual evoked potentials are decreased. Lysosomal deposits seen with electron microscopy are predominantly granular, but fingerprint and curvilinear deposits can also be seen. Classical adult-onset NCL has been designated CLN4, but the genetic basis for this disorder remains to be clarified. Recently, two patients with adult onset NCL were reported to have mutations in palmitoyl-protein thioesterase, the gene altered in classic infantile NCL (van Diggelen OP, et al 2001).

Which type of NCL does our patient most likely have?

Many patients do not precisely fit the classical types of NCL based on clinical-pathological criteria, but rather have features that cross over the previously accepted boundaries (e.g., Wisniewski et al 2001). Our patient did not speak her first words until age 2, suggesting the possibility of an early onset of neurologic involvement. However, the features of advancing disease did not become evident until near age 8. The pathologic features documented on electron microscopy were felt to be more typical of juvenile NCL, but would not exclude a late-infantile form of disease.

Editor's Note

We thank the staff of the Pediatric Neurology Service of the Texas Children's Hospital for their clinical involvement in this case. We also thank Joiner Cartwright, Ph.D., and Hannes Vogel, M.D., for their assistance with the neuropathologic diagnosis.

The challenge of the neuronal ceroid lipofuscinoses is becoming increasingly clear. As candidate genes are identified, and the phenotypic range associated with each gene defect is defined, the focus of basic research is shifting toward identifying the function(s) of the relevant proteins, and their involvement in the events that lead to cellular injury. Several methods of enzyme replacement or gene therapy are under investigation in animal models. We look forward to continuing progress toward the understanding and treatment of these devastating disorders.

-- Dennis R. Mosier, M.D., Ph.D.

References

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  9. van Diggelen OP, Thobois S, Tilikete C, et al. Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease. Ann Neurol. 2001;50:269-72.
  10. Vesa J, Hellsten E, Barnoski BL, et al. Assignment of sterol carrier protein X/sterol carier protein 2 to 1p32 and it's the causative gene for infantile neuronal lipofuscinosis. Hum Mol Genet. 1994;2:341-6.
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