Fragile X Premutation

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54.1 Clinical Features

and Laboratory Investigations Fragile X syndrome is one of the most common in- herited forms of mental retardation. The disorder is caused by an expansion in excess of 200 repeats (full mutation expansion) of a trinucleotide element, (CGG)

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, located in the 5’ untranslated region of the fragile X mental retardation 1 gene (FMR1). Trinu- cleotide expansions that are in the 55–200 repeats range are called premutations. Normal persons have a range of approximately 5–54 repeats.

Male carriers of premutations typically have nor- mal intelligence, although emotional problems and subtle physical features occur in about 25%. Mental retardation and autism may occur. About 20% of fe- male patients with a premutation experience prema- ture ovarian failure and menopause. Some female premutation carriers have emotional problems, in- cluding anxiety, obsessional thinking, or depression.

Some male carriers of the fragile X premutation over the age of 50 years experience progressive neuro- logical dysfunction with tremor and cerebellar ataxia, most frequently leading to gait difficulties and deteri- oration of fine motor skills. Additionally, progressive cognitive decline and behavioral difficulties arise, in- cluding memory loss, anxiety, mood lability, and reclusive behavior. In a few patients more serious de- mentia occurs. More variable features include parkin- sonism, peripheral neuropathy with distal weakness and sensory loss, lower limb proximal muscle weak- ness, and autonomic dysfunction with urinary and bowel incontinence and impotence. Rarely, female premutation carriers develop tremor and ataxia, but they do not experience cognitive decline.

The diagnosis of fragile X premutation is estab- lished by demonstrating a CGG repeat with a length of 55–200 trinucleotide repeats in the FMR1 gene.

54.2 Pathology

Neuropathologic findings include cerebral and cere- bellar atrophy. There are eosinophilic intranuclear in- clusions in neurons and astrocytes throughout the cortex, subcortical regions, and brain stem. The hip- pocampus and the frontal cortex are the most severe- ly affected. There is evidence of cerebellar degenera- tion with Purkinje cell loss, torpedo formation, and

dystrophic axons. Spongiform changes are seen in the cerebellar white matter and middle cerebellar pedun- cles.

54.3 Pathogenetic Considerations

The fragile X syndrome is caused by an expansion in excess of 200 repeats of a trinucleotide element, (CGG)

n

, located in the 5’ untranslated region of the fragile X mental retardation 1 gene (FMR1) on chro- mosome Xq27.3. Trinucleotide expansions that are longer than 200 repeats are called full mutation ex- pansions. Trinucleotide expansions that are in the 55–200 repeats range are called premutations. Nor- mal persons have a range of approximately 5–54 repeats.

The pathophysiology of the neurological syn- drome in older males with a premutation has not been fully understood. Repeat expansions are known to influence both transcription and translation. The full expansion of over 200 repeats generally leads to transcriptional silencing and deficiency or absence of the FMR1 protein (FMRP). Lack of this protein leads to the fragile X syndrome. In patients with a fragile X premutation, FRMP levels are gradually reduced with increasing repeat number, despite elevated FMR1 mRNA levels, suggesting that translation is impeded within the premutation range. The syndrome seen in older males with a premutation may be related to a gain of function with toxic effects related to elevated FMR1 mRNA levels.

54.4 Therapy

No specific treatment is available.

54.5 Magnetic Resonance Imaging

In older male patients carrying the fragile X premuta- tion and the clinical symptoms described above, MRI shows symmetrical signal abnormalities in the mid- dle cerebellar peduncles and deep cerebellar white matter (Figs. 54.1 and 54.2). After contrast, no en- hancement occurs. The dentate nucleus is spared.

Mild to moderate atrophy of the cerebellum, mid- brain, and pons is frequently present. Mild to moder-

Fragile X Premutation

Chapter 54

054_Valk_Fragile_X_Premutation 08.04.2005 16:09 Uhr Seite 406

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ate cerebral atrophy with thinning of the corpus cal- losum is present in the majority of the patients (Figs. 54.1 and 54.2). In many patients additional white matter abnormalities are present in the frontal

and parietal periventricular and deep white matter (Figs. 54.1 and 54.2). MRI does not demonstrate the same abnormalities in asymptomatic older male patients carrying the fragile X premutation.

54.5 Magnetic Resonance Imaging 407

Fig. 54.1. A 61-year-old man with a fragile X premutation. A CGG repeat with a length of 80 trinucleotide repeats was demonstrated in the FMR1 gene. Note the cerebral and cere- bellar atrophy. There are signal abnormalities in the middle cerebellar peduncles and deep cerebellar white matter. There

are patchy signal abnormalities in the periventricular and deep cerebral white matter. Courtesy of Dr. J. Vandevenne, Department of Radiology, and Dr. A. Wibail, Department of Neurology, Hospitals Oost-Limburg, Genk, Belgium

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Chapter 54 Fragile X Premutation 408

Fig. 54.2. A 63-year-old man with a fragile X premutation. A CGG repeat with a length of 90 trinucleotide repeats was demonstrated in the FMR1 gen.These sagittal T1-weighted im- age (first row, left) and axial FLAIR images show prominent cerebral and cerebellar atrophy. There is a periventricular rim

of elevated signal intensity. In addition, there are signal abnormalities in the base of the pons, middle cerebellar peduncles, and cerebellar white matter. Courtesy of Dr. J. Vandevenne, Department of Radiology, and Dr. I. Raets, Department of Neu- rology, Hospitals Oost-Limburg, Genk, Belgium