Customize your JAMA Network experience by selecting one or more topics from the list below.
Presenile (including juvenile and congenital) cataract is rare. Some cases have a hereditary cause; others result from trauma or chromosomal, endocrine, metabolic, or systemic disorders. Yet, a sizable percentage is of unknown cause. The disorder can occur isolated or more commonly as a part of a generalized systemic condition as well as a part of a syndrome. Genetic determination is likely, especially in the latter groups. Additional features besides the cataract should indicate the chance of a congenital disorder. Presenile cataract can be sporadic or familial. The mode of its inheritance can be dominant (principally in isolated forms) or recessive (typical in syndromic forms).1
Herein, we describe 2 siblings with early-onset cataract and additional symptoms suggesting the diagnosis of a rare, treatable disorder, cerebrotendinous xanthomatosis (CTX) (Mendelian Inheritance in Man 213700). It is an autosomal recessive lipid storage disease caused by the mutation of the CYP27A1 gene encoding the mitochondrial enzyme 27-sterol hydroxylase. The disorder results from abnormal bile acid synthesis that leads to the production of excessive cholestanol mainly but also of cholesterol to some degree. The accumulation of these sterols in different tissues, particularly in the central nervous system, leads to the varied symptoms of the disease. Traditionally, the diagnosis was based on the presence of presenile cataracts, neurological signs, chronic diarrhea, and tendon xanthomas. However, it has been suggested that the presence of 2 major symptoms (among which cataracts and neurological symptoms are the most common) should already prompt the evaluation to rule out the syndrome in affected patients.2 Indeed, recent reports indicate that the prevalence of CTX is possibly much higher than previously recognized.3
Report of Cases
A 31-year-old man (case 1) and his 32-year-old sister (case 2) were born from healthy, nonconsanguineous parents. Both of them had had surgery for presenile bilateral cataracts, which seemed to be the only common feature in their anamnesis.
Case 1. The symptoms of the man began in childhood. His early psychomotor development was delayed. However, he achieved well in school up to age 10 years when his performance deteriorated (currently, his IQ is 91 according to Raven). Persistent, chronic diarrhea; mild ataxia; and hand tremor were present since early childhood and worsened around age 18 years. Yet, results of an extensive neurological workup were normal. He also had a tendency for depression, which resulted in a suicide attempt at age 18 years. His vision began to deteriorate around age 18 years, leading to a surgery for bilateral cataracts at age 29 years. His ataxia began to worsen repeatedly at age 30 years, the reason for which another neurological workup was initiated, including a genetic evaluation.
Cranial magnetic resonance imaging results were normal, and electroencephalography showed diffuse delay. Several genetic test results (karyotype; evaluation for Friedrich ataxia, spinocerebellar ataxias, and fragile X; and mitochondrial mutation panel) were negative. Consecutively, because of the concurrent presence of presenile cataracts, complex neurological symptoms, and chronic diarrhea, the diagnosis of CTX was entertained. Biochemical analyses for serum cholestanol and urinary bile alcohol levels showed marked elevation. The diagnosis of CTX was confirmed by automated sequencing of CYP27A1 that revealed an already published (c.646G>C) and a novel (c.11_20dup) mutation in a compound heterozygous form (Table). This latter mutation causes an early frameshift and consequent amino acid sequence alterations leading to a premature stop at the 175th amino acid position of CYP27A1 (p.Arg8fsX175).
Case 2. In light of the brother's diagnosis, we recommended an evaluation for the sister also, who reportedly had surgery for cataracts at age 20 years and was healthy otherwise. However, on direct questioning, she reported to have had a photoconvulsive seizure in the same year. Additionally, she had episodic bouts of diarrhea lasting for a few days every month. She also had surgery for the removal of “lipomas” in the right popliteal region. Her physical examination disclosed no abnormalities except for scaphocephaly, mild exophthalmia, and small subcutaneous nodes in the popliteal region beside the lateral tendons. Neurological examination results were normal. However, electroencephalography showed an irregular baseline pattern and bilateral groups of slow but sharp waves. The biochemical and mutation analyses confirmed her diagnosis of CTX as well (Table).
We present a sibling pair with CTX for whom the key to their diagnosis was the presence of bilateral presenile cataracts. However, it was the existence of additional features such as neurological signs and chronic diarrhea that prompted the biochemical and genetic evaluation for CTX in both patients. Unfortunately, more than 10 years elapsed for both of them following the onset of the cataracts to their definite diagnosis. Yet, specific therapy with chenodeoxycholic acid is available,4 although its clinical efficiency (improvement/delayed progression) can differ from patient to patient. However, the earlier initiated, the better.5 Consequently, we recommend a detailed evaluation for the presence of even mild neurological, gastrointestinal, and dermal (xanthomas) disturbances in each case of presenile cataracts. The concomitant presence of even 1 associated symptom should prompt the evaluation for CTX to support early definitive therapy. Moreover, the measurement of cholestanol levels when a subject is initially seen with presenile cataracts of questionable etiology could be a valuable clinical tool.
Correspondence: Dr Kellermayer, Department of Medical Genetics and Child Development, University of Pécs, József A. u. 7., Pécs 7623, Hungary (email@example.com).
Financial Disclosure: None reported.
Tészás A, Pfund Z, Morava É, et al. Presenile Cataract: Consider Cholestanol. Arch Ophthalmol. 2006;124(10):1490–1492. doi:10.1001/archopht.124.10.1490
Coronavirus Resource Center