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Congenital ocular motor apraxia, the NPHP1 gene, and surveillance for nephronophthisis
Congenital ocular motor apraxia, the NPHP1 gene, and surveillance for nephronophthisis Brita S. Deacon, MD,a R. Scott Lowery, MD,a Paul H. Phillips, MD,a and G. Bradley Schaefer, MDb
We present an 11-month-old girl with congenital ocular motor apraxia (COMA) and Joubert syndrome found to have a compound heterozygous mutation in the NPHP1 gene that is responsible for juvenile nephronophthisis type 1. The association of congenital ocular motor apraxia and juvenile nephronophthisis is reviewed. The patient does not currently manifest signs of renal failure, although her mutation indicates that she is at risk for the development of juvenile nephronophthisis type 1.
milestones but participated in physical and occupational therapy. She was referred to our geneticist for further evaluation and genetic testing, which showed a compound heterozygous mutation of the gene for juvenile nephronophthisis, the NPHP1 gene. One allele had a large deletion and the other a point mutation. The findings of baseline renal ultrasound and renal function tests were normal.
Case Report
Discussion
A
Congenital ocular motor apraxia is characterized by the absence of voluntary horizontal saccades. Patients manifest large head thrusts to compensate for deficient horizontal saccades and to refixate on a target. When fixation is achieved, the head slowly returns to a neutral position to allow direct gaze of the new target. Vertical saccades are preserved. The signs typically improve over time.2 Most cases of COMA are sporadic, but familial cases suggestive of autosomal-dominant and -recessive patterns of inheritance have been described.3 Although the etiology of COMA is unknown, the disorder may be associated with central nervous system abnormalities, including cerebellar vermis hypoplasia, perinatal and acquired infections, tumors, or hypoxia.2 There have been few reports of COMA associated with systemic disease outside the central nervous system. Betz and colleagues4 described 2 patients with COMA and juvenile nephronophthisis type 1, an autosomalrecessive kidney disease that results in renal failure in adolescence. The first patient was diagnosed with COMA at 5 years of age and developed polyuria and polydipsia at 7 years of age. A kidney biopsy at 20 years of age confirmed the diagnosis of nephronophthisis. The second patient was diagnosed with COMA in his first year of life and developed polyuria and polydipsia from nephronophthisis at 9 years of age. Gene deletions on the NPHP1 gene located on chromosome 2q13 occur in about 85% of patients with nephronophthisis.5 Both patients described by Betz and colleagues4 had gene deletions in the NPHP1 gene. One patient had large deletions on both chromosomes for NPHP1; the other had a heterozygous combination of a large deletion on one chromosome and a point mutation on the other.4 Saunier and colleagues described 4 patients with COMA, nephronophthisis type 1, and deletions of the NPHP1 gene, but clinical details are not provided (Saunier S, et al. Large deletions of the NPH1 region in Cogan syndrome [CS] associated with familial juvenile nephronophthisis. Am J Hum Genet 1997;61:A346 [abstract]). Neuroimaging was not reported for the cases of
n 11-month-old girl presented to the Arkansas Children’s Hospital for evaluation of “poor tracking” since birth. Her medical history was remarkable for developmental delay and possible seizures. She had no breathing abnormalities during the perinatal period. On ophthalmological examination, fixation was central, steady, and maintained in both eyes. She was orthotropic, with full ductions in response to vestibular stimulation induced by forced head rotation; however, she was unable to initiate horizontal saccades and performed horizontal head thrusts to change fixation, consistent with congenital ocular motor apraxia (COMA). External, slit-lamp and funduscopic examination were normal, with no coloboma or signs of a retinal dystrophy. Magnetic resonance imaging of the brain with gadolinium was initially interpreted as normal; however, further review disclosed mild dysplasia of the superior cerebellar vermis and hypertrophy of the superior cerebellar peduncles consistent with a “molar tooth” deformity (Figure 1). The combination of COMA, developmental delay, and the molar tooth deformity established a diagnosis of Joubert syndrome.1 At 5 years of age, the patient’s best-corrected visual acuity was 20/20 in both eyes by HOTV testing. There was no change in the remainder of her ophthalmologic findings. She remained delayed in her developmental Author affiliations: Departments of aOphthalmology and bPediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, Arkansas Supported in part by an unrestricted grant from Research to Prevent Blindness (New York, NY) and the Pat & Willard Walker Eye Research Center, Jones Eye Institute, University of Arkansas for Medical Sciences (Little Rock, AR). Submitted August 1, 2012. Revision accepted February 19, 2013. Published online May 20, 2013. Correspondence: Paul H. Phillips, MD, Arkansas Children’s Hospital, 1 Children’s Way-Slot 111, Little Rock, AR 72202 (email: [email protected]). J AAPOS 2013;17:332-333. Copyright Ó 2013 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2013.02.003
332
Journal of AAPOS
Volume 17 Number 3 / June 2013
Deacon et al
333
Our patient is the second reported case of a large deletion and point mutation of the NPHP1 gene in association with COMA. Our patient does not yet have a diagnosis of nephronophthisis. However, she may be too young to manifest signs and symptoms of nephronophthisis, as these typically occur in later childhood or early adolescence. Our knowledge of her NPHP1 gene mutation has prompted us to monitor her for the development of renal disease with renal function testing every 6 months. Nephronophthisis has been associated with NPHP1 gene mutations in patients with Joubert syndrome.1,6 Patients with Joubert syndrome and the NPHP1 gene mutation often have a mild form of the molar tooth deformity similar to that in our patient.1 In addition, COMA is one of the salient ocular motor signs in patients with Joubert syndrome.6 Our patient’s findings suggest that it may be reasonable to screen patients diagnosed with COMA for deletions of the NPHP1 gene. Patients with deletions should be monitored with renal function testing. Early detection of renal failure can diminish the consequences, such as anemia, growth failure, and chronic acidosis.
References
FIG 1. Cranial magnetic resonance imaging of 11-month-old girl with congenital ocular motor apraxia. A, Sagittal, T1-weighted image showing mild dysplasia of the superior vermis (arrow). B, Axial, T1-weighted image showing hypertrophy of the superior cerebellar peduncles forming the “molar tooth” deformity (arrow).
COMA described by Betz and colleagues4 and Saunier and colleagues; thus it is unknown whether these patients had a molar tooth deformity consistent with Joubert syndrome.
Journal of AAPOS
1. Parisi MA. Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C Semin Med Genet 2009;151C: 326-40. 2. Brodsky MC. Complex ocular motor disorders in children. In: Brodsky MC, editor. Pediatric Neuro-ophthalmology. 2nd ed. New York: Springer; 2010:309-66. 3. Phillips PH, Brodsky MC, Henry PM. Congenital ocular motor apraxia with autosomal dominant inheritance. Am J Ophthalmol 2000;129:820-22. 4. Betz R, Rensing C, Otto E, et al. Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis. J Pediatr 2000;136:828-31. 5. Saunier S, Calado J, Benessy F, et al. Characterization of the NPHP1 locus: Mutational mechanism involved in deletions in familial juvenile nephronophthisis. Am J Hum Genet 2000;66: 778-89. 6. Couch SM, Brodie SE, Leavitt JA, Brodsky MC. Something to sink your teeth into. Surv Ophthalmol 2011;56:544-9.
We present an 11-month-old girl with congenital ocular motor apraxia (COMA) and Joubert syndrome found to have a compound heterozygous mutation in the NPHP1 gene that is responsible for juvenile nephronophthisis type 1. The association of congenital ocular motor apraxia and juvenile nephronophthisis is reviewed. The patient does not currently manifest signs of renal failure, although her mutation indicates that she is at risk for the development of juvenile nephronophthisis type 1.
milestones but participated in physical and occupational therapy. She was referred to our geneticist for further evaluation and genetic testing, which showed a compound heterozygous mutation of the gene for juvenile nephronophthisis, the NPHP1 gene. One allele had a large deletion and the other a point mutation. The findings of baseline renal ultrasound and renal function tests were normal.
Case Report
Discussion
A
Congenital ocular motor apraxia is characterized by the absence of voluntary horizontal saccades. Patients manifest large head thrusts to compensate for deficient horizontal saccades and to refixate on a target. When fixation is achieved, the head slowly returns to a neutral position to allow direct gaze of the new target. Vertical saccades are preserved. The signs typically improve over time.2 Most cases of COMA are sporadic, but familial cases suggestive of autosomal-dominant and -recessive patterns of inheritance have been described.3 Although the etiology of COMA is unknown, the disorder may be associated with central nervous system abnormalities, including cerebellar vermis hypoplasia, perinatal and acquired infections, tumors, or hypoxia.2 There have been few reports of COMA associated with systemic disease outside the central nervous system. Betz and colleagues4 described 2 patients with COMA and juvenile nephronophthisis type 1, an autosomalrecessive kidney disease that results in renal failure in adolescence. The first patient was diagnosed with COMA at 5 years of age and developed polyuria and polydipsia at 7 years of age. A kidney biopsy at 20 years of age confirmed the diagnosis of nephronophthisis. The second patient was diagnosed with COMA in his first year of life and developed polyuria and polydipsia from nephronophthisis at 9 years of age. Gene deletions on the NPHP1 gene located on chromosome 2q13 occur in about 85% of patients with nephronophthisis.5 Both patients described by Betz and colleagues4 had gene deletions in the NPHP1 gene. One patient had large deletions on both chromosomes for NPHP1; the other had a heterozygous combination of a large deletion on one chromosome and a point mutation on the other.4 Saunier and colleagues described 4 patients with COMA, nephronophthisis type 1, and deletions of the NPHP1 gene, but clinical details are not provided (Saunier S, et al. Large deletions of the NPH1 region in Cogan syndrome [CS] associated with familial juvenile nephronophthisis. Am J Hum Genet 1997;61:A346 [abstract]). Neuroimaging was not reported for the cases of
n 11-month-old girl presented to the Arkansas Children’s Hospital for evaluation of “poor tracking” since birth. Her medical history was remarkable for developmental delay and possible seizures. She had no breathing abnormalities during the perinatal period. On ophthalmological examination, fixation was central, steady, and maintained in both eyes. She was orthotropic, with full ductions in response to vestibular stimulation induced by forced head rotation; however, she was unable to initiate horizontal saccades and performed horizontal head thrusts to change fixation, consistent with congenital ocular motor apraxia (COMA). External, slit-lamp and funduscopic examination were normal, with no coloboma or signs of a retinal dystrophy. Magnetic resonance imaging of the brain with gadolinium was initially interpreted as normal; however, further review disclosed mild dysplasia of the superior cerebellar vermis and hypertrophy of the superior cerebellar peduncles consistent with a “molar tooth” deformity (Figure 1). The combination of COMA, developmental delay, and the molar tooth deformity established a diagnosis of Joubert syndrome.1 At 5 years of age, the patient’s best-corrected visual acuity was 20/20 in both eyes by HOTV testing. There was no change in the remainder of her ophthalmologic findings. She remained delayed in her developmental Author affiliations: Departments of aOphthalmology and bPediatrics, University of Arkansas for Medical Sciences, Arkansas Children’s Hospital, Little Rock, Arkansas Supported in part by an unrestricted grant from Research to Prevent Blindness (New York, NY) and the Pat & Willard Walker Eye Research Center, Jones Eye Institute, University of Arkansas for Medical Sciences (Little Rock, AR). Submitted August 1, 2012. Revision accepted February 19, 2013. Published online May 20, 2013. Correspondence: Paul H. Phillips, MD, Arkansas Children’s Hospital, 1 Children’s Way-Slot 111, Little Rock, AR 72202 (email: [email protected]). J AAPOS 2013;17:332-333. Copyright Ó 2013 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/$36.00 http://dx.doi.org/10.1016/j.jaapos.2013.02.003
332
Journal of AAPOS
Volume 17 Number 3 / June 2013
Deacon et al
333
Our patient is the second reported case of a large deletion and point mutation of the NPHP1 gene in association with COMA. Our patient does not yet have a diagnosis of nephronophthisis. However, she may be too young to manifest signs and symptoms of nephronophthisis, as these typically occur in later childhood or early adolescence. Our knowledge of her NPHP1 gene mutation has prompted us to monitor her for the development of renal disease with renal function testing every 6 months. Nephronophthisis has been associated with NPHP1 gene mutations in patients with Joubert syndrome.1,6 Patients with Joubert syndrome and the NPHP1 gene mutation often have a mild form of the molar tooth deformity similar to that in our patient.1 In addition, COMA is one of the salient ocular motor signs in patients with Joubert syndrome.6 Our patient’s findings suggest that it may be reasonable to screen patients diagnosed with COMA for deletions of the NPHP1 gene. Patients with deletions should be monitored with renal function testing. Early detection of renal failure can diminish the consequences, such as anemia, growth failure, and chronic acidosis.
References
FIG 1. Cranial magnetic resonance imaging of 11-month-old girl with congenital ocular motor apraxia. A, Sagittal, T1-weighted image showing mild dysplasia of the superior vermis (arrow). B, Axial, T1-weighted image showing hypertrophy of the superior cerebellar peduncles forming the “molar tooth” deformity (arrow).
COMA described by Betz and colleagues4 and Saunier and colleagues; thus it is unknown whether these patients had a molar tooth deformity consistent with Joubert syndrome.
Journal of AAPOS
1. Parisi MA. Clinical and molecular features of Joubert syndrome and related disorders. Am J Med Genet C Semin Med Genet 2009;151C: 326-40. 2. Brodsky MC. Complex ocular motor disorders in children. In: Brodsky MC, editor. Pediatric Neuro-ophthalmology. 2nd ed. New York: Springer; 2010:309-66. 3. Phillips PH, Brodsky MC, Henry PM. Congenital ocular motor apraxia with autosomal dominant inheritance. Am J Ophthalmol 2000;129:820-22. 4. Betz R, Rensing C, Otto E, et al. Children with ocular motor apraxia type Cogan carry deletions in the gene (NPHP1) for juvenile nephronophthisis. J Pediatr 2000;136:828-31. 5. Saunier S, Calado J, Benessy F, et al. Characterization of the NPHP1 locus: Mutational mechanism involved in deletions in familial juvenile nephronophthisis. Am J Hum Genet 2000;66: 778-89. 6. Couch SM, Brodie SE, Leavitt JA, Brodsky MC. Something to sink your teeth into. Surv Ophthalmol 2011;56:544-9.