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Differential Diagnosis

This 6 year old boy had profound motor and intellectual deterioration, with cortical and pseudobulbar manifestations, beginning at 1-2 years of age and subsequent onset of a mixed-seizure disorder (possibly myoclonus epilepsy). In addition, he was said to have manifested discrete, presumably foveal, patches of cherry-red retina in both retinas. These deficits are referable bilaterally to the retina, cerebral cortex, supranuclear descending fiber tracts (especially at the level of the midbrain), and cerebellum or its connections. It is important that no marked dysmorphism, organomegaly, or dysostosis was found.

This boy's early intellectual development was not entirely normal. He had a relatively slow phase of psychomotor decline between the ages of two and five years, with frequent falls. The history does not permit us to differentiate among ataxia, dystonia, weakness, spasticity, spells of atony, and visual difficulties as the cause of the falls. Repeated bouts of tonsillitis permit us to rule out ataxia telangiectasia.

Shortly before the patient's fifth birthday, seizures developed. They were initially tonic and subsequently atonic, and they increased in frequency. In a child with ataxia and neurologic degeneration, this sequence suggests a progressive myoclonus epilepsy. Poor feeding (despite a good appetite and preserved lower-cranial-nerve function), barely intelligible speech, uncertain proximal strength, intact sensation of pain, pyramidal signs, and inability to maintain a vertical posture are nonspecific findings in childhood neurodegenerative diseases. We have three important diagnostic clues, all of which are related to the visual system: the presence of cherry-red spots, limitation of the gaze, and reduced visual acuity, with concentric reduction of the visual field.

A few test results are more helpful for ruling out diagnostic possibilities than for supporting their inclusion in the differential diagnosis. In this case, it is important that the cerebrospinal fluid protein level and immune profile and the peripheral-nerve conduction velocities were normal. On electroencephalography, the voltage of somatosensory evoked potentials was very high; this finding is most helpful in suggesting a diagnosis.

The axial T₂-weighted MRI studies show two abnormalities. The white matter is hyperintense on T₂-weighted images — a finding that is nonspecific but very abnormal in a person of this age. The ventricles and the sulci are prominent, indicating the presence of generalized atrophy. On the coronal T₁-weighted images, there is a thin, periventricular band of hypointensity bilaterally; it is similar in intensity to the cortical gray matter. The distinctive visual abnormalities in this case are specific diagnostic clues, but they lead in different directions.

The term “cherry-red spot” refers to the normal hue of the fovea, which may be thrown into startling relief in some storage disorders that produce a pallid perifoveal ring. It is a characteristic finding of lysosomal storage diseases. The hue of the normal fovea, and likewise that of the cherry-red spot, varies according to the pigmentary-gene complement and ranges from pale pink to the cherry black that may be seen in dark-skinned persons. If an abnormal perifoveal ring is present, we can be almost certain that the patient has 1 of about 15 storage diseases. Cherry-red spots may result from Fabry's disease or from vascular disorders such as stroke, incontinentia pigmenti, trauma, or toxicity (in which the spots are often unilateral or asymmetric). All these conditions can be ruled out in this case. Other macular abnormalities — particularly the bull's-eye maculopathy associated with late-onset infantile neuronal ceroid lipofuscinosis — may resemble cherry-red spots, so a precise description of the lesion is essential.

A finite group of diseases in which cherry-red spots are found include the sialidoses, GM₁ and GM₂ gangliosidoses, Niemann–Pick disease (Crocker groups A through D but not E and F), Farber's lipogranulomatosis, and metachromatic leukodystrophy. Cherry-red spots are not present in all cases of these disorders, and in cases in which they are present the spots may appear, disappear, or change in hue. Their appearance and disappearance are influenced by the accumulation of storage material in the lysosomes of the perifoveal ganglion cells. Changes in hue may be related to secondary macular deterioration, as in some patients with Tay–Sachs disease.

The appearance of the perifoveal change is important in the differential diagnosis and depends on the types and amounts of material stored in the perifoveal ganglion cells. In Tay–Sachs disease and Sandhoff's disease, the considerable amount of stored material produces an opalescent white ring. In Niemann–Pick disease, the ring is more diffuse and may have less distinct margins; it may even be patchy. The faint, gray ring of Farber's lipogranulomatosis and of metachromatic leukodystrophy may render the cherry-red spot more difficult to visualize.

We can rule out many of the aforementioned diseases, either because they are manifested earlier or later than the disease in this case or because the pattern of neurologic dysfunction is dissimilar to that observed in this patient. Other diseases that can be ruled out are associated with storage of gangliosides or other substances in other parts of the body, producing a so-called mucopolysaccharidosis phenotype that includes facial dysmorphism, organomegaly, dysostosis multiplex, and inguinal hernias.

Patients with group B Niemann–Pick disease have massive organomegaly and are neurologically normal. The few cases of group B disease involving mild ataxia or mental retardation have proved to be misdiagnosed cases of group C disease. Type I sialidosis, myoclonus, cherry-red spots, and severe impairment of motor-system function develop in adolescence, and the vision and intellect typically are normal. Patients with type II sialidosis (congenital or infantile sialidosis or galactosialidosis) have an extreme mucopolysaccharidosis phenotype. Type I GM₁ gangliosidosis (previously called Norman–Landing disease) is characterized by severe neurologic failure in infancy with a marked mucopolysaccharidosis phenotype. Both acute infantile forms of GM₂ gangliosidosis (classic Tay–Sachs disease and Sandhoff's disease), the most common causes of cherry-red spots, must be ruled out in this case, regardless of the presence or absence of organomegaly. They have an infantile onset with macrocephaly, and the type and severity of their neurologic manifestations differ from those in the present case.

None of the six variant forms of Farber's lipogranulomatosis (including type IV, which may be associated with cherry-red spots) belong in the differential diagnosis. Metachromatic leukodystrophy may also be associated with cherry-red spots and with ataxia, speech deterioration, and episodes of hypertonus, which could have caused this patient to lose his balance and fall. The absence of any peripheral-nerve involvement rules out this diagnosis.

Subacute GM₂ gangliosidosis of either the Tay–Sachs or Sandhoff's biochemical profile has a late infantile or juvenile onset and is associated with ataxia, incoordination, loss of speech, loss of self-care skills, dementia, spasticity, and seizures that progress at variable rates. Cherry-red spots are seldom present, however, although optic atrophy and retinitis pigmentosa may develop. Although most patients with group C Niemann–Pick disease have organomegaly, it may be overlooked. The characteristically mild delay in early development and the frequent falls, speech difficulties, ataxia, and dysphagia tend to occur at the same ages as they occurred in the child in the current case; however, children with group C Niemann–Pick disease usually have neonatal jaundice.

This patient's gaze difficulties are an important reason to retain subacute GM₂ gangliosidosis and especially Crocker group C Niemann–Pick disease in the differential diagnosis. The features of this case are consistent with those of Wernicke's pseudo-ophthalmoplegia, a manifestation of pseudobulbar palsy. Pseudobulbar palsy is also the likely explanation of this child's speech and feeding difficulties. Vertical supranuclear limitation can be localized to the midbrain pretectal portion of the rostral medial longitudinal fasciculus. Many of the known causes of this dysfunction can be dismissed on the basis of the history in this case.

Supranuclear gaze palsy, particularly that affecting the vertical gaze (downward saccades more than upward), is particularly characteristic of Crocker group C Niemann–Pick disease. Most cases of so-called juvenile dystonic lipidosis, which also characteristically produces supranuclear vertical-gaze palsy, have also been examples of group C Niemann–Pick disease, although some are atypical cases of neuronal ceroid lipofuscinosis. There is a single case report of a supranuclear gaze palsy in a patient with Kufs' disease, or adult-onset neuronal ceroid lipofuscinosis. Supranuclear gaze palsy has also been described in late-onset, chronic variants of GM₂ gangliosidosis. The absence of organomegaly weighs against group C Niemann–Pick disease or juvenile dystonic lipidosis.

Pseudobulbar gaze palsy may occur in metachromatic leukodystrophy, but usually at a late stage of severe illness and in association with bulbar signs. In the current case, the normal level of protein in the cerebrospinal fluid and the normal nerve-conduction velocities argue against the infantile form of leukodystrophy. A case of infantile Krabbe's disease with a cherry-red spot has been described.

Diminished visual acuity with restriction of the visual fields suggests the presence of tapetoretinal degeneration and would be an unusual manifestation of a disease producing cherry-red spots. Visual loss is characteristic of gangliosidosis — hence the former labeling of Tay–Sachs disease as “amaurotic idiocy” — but it is predominantly cortical rather than retinal. Retinal changes may be seen in late-onset GM₂ gangliosidosis, which may in some instances resemble those of neuronal ceroid lipofuscinosis. Retinal degeneration in mitochondrial encephalomyopathic disease is not suggested by the features of this case, and mitochondrial degeneration produces ophthalmoplegia rather than pseudo-ophthalmoplegia.

Neuronal ceroid lipofuscinosis accounts for the remaining disorders formerly classified as amaurotic idiocy. These conditions are so difficult to distinguish from the gangliosidoses that we must rely on the presence or absence of cherry-red spots to diagnose the infantile forms and on electroretinographic findings to diagnose forms with a later onset. In the current patient, the retinal disease that gave rise to the visual-field loss as well as the progressive myoclonus epilepsy are far more consistent with the late-onset infantile (Janský–Bielschowsky) form of neuronal ceroid lipofuscinosis than with any of the diagnoses associated with cherry-red spots. This diagnosis also provides an explanation for the large evoked potentials and the high-amplitude electroencephalographic changes in this case, which could otherwise be explained only by type I sialidosis.

Thus, an important question in this case is whether the patient's cherry-red spots are actually a ganglion-cell storage disorder producing bull's-eye maculopathy of the type associated with late-onset infantile neuronal ceroid lipofuscinosis. The late-onset infantile form of neuronal ceroid lipofuscinosis causes macular dystrophy, rather than the retinitis pigmentosa found in patients with later-onset ceroid lipofuscinosis (Batten disease or Vogt–Spielmeyer disease). The bull's-eye macula is often clearly demarcated from a surrounding area of hypopigmented retina and usually shows pigmentary clumping, particularly at its margins. This child may have had relatively dark skin, which may be associated with unusually uniform pigmentary clumping at the macula, resulting in a usually convincing, false cherry-red spot. First described in 1933, the bull's-eye maculae of Janský–Bielschowsky disease may be brown, reddish brown, or mottled and are sometimes surrounded by a gray zone.3

Photographs of the retina were taken only after the diagnostic procedure had been performed.

The photographs show a gray ring, or halo, in the perifoveal area, setting apart a fovea that appears cherry red.

However, the pigmentation of the fovea is not uniform, suggesting pigmentary clumping at the margins. These features indicate that the lesion is better interpreted as bull's-eye maculopathy, which is typical of late-infantile neuronal ceroid lipofuscinosis. This interpretation is more consistent with this patient's epilepsy, visual-field restriction, and electrophysiological abnormalities than with disorders associated with true cherry-red spots. If we return to the fact that this child had high-amplitude visual evoked cortical responses, the diagnosis is all but certain.

The patient's ethnicity (Iranian- Middle Eastern origin) also suggests this diagnosis. In some areas of the Middle East, the rate of first-cousin marriages exceeds 50 percent, and autosomal recessive ceroid lipofuscinosis is among the most common neurodegenerative diseases.

The most direct method for establishing this diagnosis is electroretinography. If there is no retinal response to electroretinography, electron-microscopical examination of biopsy specimens of the conjunctiva or of eccrine-gland–containing tissues may show the diagnostic curvilinear bodies containing abnormal lysosomal-storage material. Genetic testing could also confirm the diagnosis.

When the patient was examined first, visualization of the fundi was not completely achieved, except to note that they appeared pale. The discovery of cherry-red spots by an ophthalmologic consultant turned our attention to the neuronal ceroid lipofuscinosis. We favored the diagnoses of Sandhoff's variant of GM₂ gangliosidosis and neuronal ceroid lipofuscinosis. However, another possibility, mitochondrial encephalomyelopathy, dictated our choice of diagnostic procedure. 

Clinical Diagnosis

Neuronal ceroid lipofuscinosis, late-onset infantile subtype (Janský–Bielschowsky disease).

Pathological Discussion

The diagnostic procedure was a biopsy of the left quadriceps muscle and of the sural nerve. Microscopical examination of the muscle-biopsy specimen revealed only slight variation in the size of the myofibers.

An acid phosphatase stain showed reddish granular deposits within the myofibers, indicating an increase in lysosomal activity. Light-microscopical examination of the nerve was unremarkable.

Neuronal ceroid lipofuscinosis is a heterogeneous group of progressive, neurodegenerative disorders that occur in children and, less commonly, in adults. In most cases, these disorders have an autosomal recessive mode of inheritance, with rare cases of autosomal dominant inheritance occurring in adults. The overall incidence of neuronal ceroid lipofuscinosis worldwide is 1 in 12,500 live births. Clinically, these disorders are characterized by visual loss, epilepsy, and psychomotor deterioration. The classification of these disorders is based on age at onset, clinical features, morphologic features on ultrastructural examination, and genetic subtype.

The characteristic morphologic lesions of neuronal ceroid lipofuscinosis are the loss of neurons and widespread intracellular accumulation of lipid pigment within neurons and other types of cells, including lymphocytes and cells of the vascular endothelium, sweat-gland epithelium, and muscle. The degree of neuronal loss varies according to the subtype of the disorder. Despite the accumulation of intracellular lipid pigment, neurons do not have the “ballooned” appearance that is seen in other storage disorders. The lipid pigment characteristically stains with Luxol fast blue, Sudan black, and periodic acid–Schiff. In ultraviolet light, the material has a yellow to silvery autofluorescence that differs from the orange autofluorescence of lipofuscin. Although the ultrastructural characteristics of the lipid pigment are not pathognomonic of specific subtypes of the disease, particular forms are present in each subtype. Curvilinear bodies are the only form in which lipid pigment is found in classic late-onset infantile neuronal ceroid lipofuscinosis (the CLN2 subtype). The storage material is membrane-bound, a feature that is consistent with its localization within lysosomes. Subunit c of mitochondrial ATP synthase is the primary component of the lipid pigment in the CLN2, CLN3, and CLN4 subtypes, whereas sphingolipid activator proteins A and D predominate in the CLN1 subtype.

In the current case, the boy's age at the onset of disease, the clinical presentation, and the ultrastructural features are most consistent with the classic late-onset infantile subtype of neuronal ceroid lipofuscinosis (the CLN2 subtype). The CLN2 gene is located on chromosome 11p15. In one study, an intronic mutation (in which cytosine was substituted for guanine at position T523-1), affecting a splicing junction, and a nonsense mutation (in which thymine was substituted for cytosine at position 636) were found, singly or together, in 69 percent of patients. The CLN2 gene product is homologous to tripeptidyl peptidase I (TPP-I), a lysosomal, pepstatin-insensitive exopeptidase that cleaves tripeptides from the N terminal of oligopeptides and proteins. TPP-I activity is deficient in the fibroblasts and brain tissue of patients with this type of the disorder. It has been hypothesized that subunit c of mitochondrial ATP synthase is a substrate for TPP-I and that the accumulation of subunit c is a result of deficient TPP-I activity.

Because the abnormal lipid pigment accumulates in many types of cells, ultrastructural examination of many tissues may be diagnostically useful. Prenatal diagnosis is based on the examination of chorionic or amniotic cells for the presence of the abnormal storage material or decreased enzyme activity or by mutational or haplotype analysis and comparison of the results with those in the reference patient

Tests for arylsulfatase A, very-long-chain fatty acids, and β-galactosidase were negative. Oligosaccharide screening was negative. Genetic tests for two of the mutations implicated in neuronal ceroid lipofuscinosis were negative. Electroretinography demonstrated attenuated responses to stimulation that were consistent with advanced diffuse retinal degenerations preferentially affecting cone photoreceptor function, strongly favoring a diagnosis of neuronal ceroid lipofuscinosis.

The patient had a younger sister, who was about seven months old at the time of his diagnosis. The sister appeared clinically normal at that time, but we have no further information.

           The FINAL Diagnosis                       تشخیص       

Neuronal ceroid lipofuscinosis,

 late-onset infantile subtype

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