The genetic spectrum of congenital ocular motor apraxia type Cogan: an observational study, continued

In this cohort of 21 patients with COMA, molecular genetic investigations including WES, panel, or single gene analyses revealed causative genetic findings in 17 subjects. The clinical and neuroimaging diagnosis of JBTS established in 11 subjects was confirmed in nine patients by causative molecular genetic findings. In two individuals with clear MTS on neuroimaging no conclusive genetic result was obtained, using WES. Two other patients without definite MTS arrived at a genetic diagnosis of JBTS4 and JBTS23 due to pathogenic variants in the NPHP1 and KIAA0586 gene, respectively. This observation sheds new light on the doctrinal statement, that the neuroimaging feature of MTS is a prerequisite for the diagnosis of JBTS. In this study we found both, subjects with and without definite MTS to carry pathogenic biallelic mutations in NPHP1 or KIAA0586, two bona fide JBTS genes. Apart from the methodological issues which might compromise recognition of the MTS (technically appropriate MRI, expert assessment), increasing evidence indicates that the ciliopathic midbrain-hindbrain malformations do not allow for a clear-cut separation between MTS and normal. Instead, they rather shape a spectrum of anomalies with smooth transitions between normal and strikingly abnormal morphology of brainstem and cerebellum, as exemplary observed in SUFU-associated conditions [6, 12]. However, we would like to emphasize, that, as a rule, in JBTS the large majority of patients have a typical MTS; neuroimaging features resembling a mild MTS (as discussed below with SUFU-associated conditions) are occasionally observed, and normal MRI is exceptionally rare.

In three patients with mild cerebellar abnormalities including prominent, thickened, elongated superior cerebellar peduncles, vermis folia dysplasia and upper vermis split, but without definite MTS on MRI, we detected heterozygous truncating mutations in the SUFU gene. Together with further patients recruited subsequently, these subjects represent the first examples of a newly identified forme fruste of JBTS [6]. More recently, additional 22 patients with SUFU haploinsufficiency and a neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum were reported [12]. All these patients had persistent COMA.

Among those 11 subjects of our cohort, who carried causative mutations associated with any of the subtypes of JBTS, KIAA0586 was the gene most frequently affected. Although KIAA0586 was recognized to be one of the most prevalent six JBTS genes [13], the prevalence of KIAA0586-associated JBTS23 among all JBTS subtypes was estimated to be 2.5% [14], 5% [15] and 7% [13] in large cohorts of JBTS patients reported previously. In this respect, the high prevalence of 19% (6 individuals from 4 out of 21 families) in our COMA cohort is surprising. We cannot explain why KIAA0586 is prevailing in our cohort and presume that this is likely a coincidental finding. While some of the abovementioned previous studies provided information on the prevalence of retinal dystrophy and coloboma in the different subtypes of JBTS, no such date are available for COMA.

Of note, in one subject (#18) with recognition of COMA as early as 4 months of age we identified two variants in the ATM gene in compound heterozygous state [7]. While the pathogenicity of the splice-donor site variant c.2250G > A, resulting in skipping of exon 14, was already convincingly documented, it was a matter of longstanding debate whether the 2nd variant, the splice-acceptor site variant c.1066-6T > G, is disease-causing. This variant leads to “leaky” splicing of exon 11 and thus to exon skipping, thereby to frameshift and premature protein truncation. In a separate study we showed that these two variants in compound heterozygous state lead to reduced expression of ATM protein and residual activity of the ATM kinase at a level consistent with variant ataxia-telangiectasia (A-T) [7]. To our knowledge, this is the first report of ocular motor apraxia as the initial symptom of A-T.

Patient #7 showed characteristic features of Poretti-Boltshauser syndrome (PTBHS) on neuroimaging, and detection of a homozygous pathogenic variant in LAMA1 confirmed this diagnosis. Ocular motor apraxia was reported to be part of the clinical phenotype in PBS already in the first description [16] as well as in subsequent publications [4] and is listed in the Clinical Synopsis of PTBHS in OMIM.

Although the number of patients with COMA gathered in this cohort is small, the genetic findings reported here depict a somewhat representative spectrum of genetic etiologies in COMA. When we recruited our cohort of patients diagnosed as having COMA, we excluded all subjects with a pre-existing diagnosis of JBTS, based on recognition of the MTS in neuroimaging [2]. Thus, our cohort has a clear bias towards diverse rare causes of COMA, others than JBTS. However, the genetically heterogeneous group of JBTS accounts by far for the most cases of COMA [17].

OMIM currently lists 40 different genetically defined subtypes of JBTS. For 27 of these subtypes, ocular apraxia is specified as a clinical feature in the Clinical Synopsis of the respective JBTS subtype in OMIM. For further four JBTS subtypes, a PubMed search retrieves reports of ocular apraxia as part of the clinical phenotype (type 9 [18]; type 23 [5, 15] and this report; type 26 [19], and type 30 [20]). In addition, a recent review of ocular manifestations of JBTS [21] listed ocular apraxia as a clinical feature in further two subtypes of JBTS, namely types 10 and 13, associated with OFD1 and TCTN1.

For the remaining seven subtypes of JBTS, a PubMed search using the term “ocular apraxia” and the name of the respective gene does not detect any hits. However, when novel associations of a JBTS phenotype with a particular gene were reported, some of these papers strongly focus on the molecular genetic results and other laboratory tests. The clinical features were mentioned more in passing in these reports. Furthermore, several of these genetic reports described only single families. Occasionally, “abnormal eye movements” are listed among the clinical features, which may include ocular apraxia. Thus, ocular apraxia might occur in additional subtypes of JBTS [22].

In a textbook of neuroophthalmology published in 2010 [23], COMA was ascribed to three major clinical conditions:

1.

A benign (“idiopathic”) variant with normal findings in both, neurological examination and neuroimaging, but occasional muscular hypotonia, motor and speech delay, as well as ataxia;

2.

A variant with non-progressive, “non-inherited” structural brain anomaly due to either a developmental aberration or acquired lesion, e.g., dysgenesis of the cerebellar vermis or corpus callosum, Dandy–Walker malformation, gray matter heterotopias, or hypoxic-ischemic encephalopathy; and

3.

A spectrum of genetic multisystem disorders including JBTS, Jeune syndrome, and a subset of patients with Leber congenital amaurosis [23].

Our observations reported here together with evidence emerging over the past decade indicate that the borders of these three categories are blurring. E. g., the “benign, idiopathic” variant (1) with muscular hypotonia, mild developmental delay, and ataxia fits well with the forme fruste of JBTS associated with heterozygous truncating SUFU variants [6, 12]. These patients do show nonprogressive structural brain anomalies (2) comprising vermis folia dysplasia and upper vermis split discernible on neuroimaging, and there is a smooth transition to definite JBTS (3) with a full-blown MTS.

Taken together, our results show that COMA presents a neurological symptom with marked etiologic heterogeneity. Genetic causes by far outnumber acquired conditions, and among the inherited ailments, the genetically heterogeneous group of Joubert syndromes account for the vast majority of OMA with onset in infancy.

Based on these data we propose the following recommendations for the diagnostic approach in patients with COMA: Once the symptom of early-onset ocular motor apraxia is assured by a pediatric neurologist or neuroophthalmologist or both, further diagnostic steps should be initiated, if not already performed. Regional and local availabilities may shape the sequence of these investigations. Advisable are

1.

a thorough physical examination with focus on congenital anomalies, e.g. polydactyly, thoracic dysplasia, other skeletal dysplasia,

2.

an ophthalmological examination with focus on retinal dystrophy and coloboma,

3.

MRI of the brain in technical quality (angulation, slice thickness) adequate for assessment of especially brainstem and cerebellum, and review of this MRI by a neuroradiologist or neurologist with experience in pediatric posterior fossa diseases, particularly malformations.

Figure 1 provides an algorithm for the diagnostic approach in COMA.

Fig. 1figure 1

Algorithm for the diagnostic approach in COMA. NGS next generation sequencing, SCP superior cerebellar peduncles, WES whole exome sequencing

The main diagnostic procedure in patients with early-onset ocular motor apraxia is a molecular genetic investigation using NGS-based approaches. Both, a specific multi-gene panel analysis or an whole exome sequencing (WES) strategy can be performed. The reason why the authors prefer an initial multi-gene panel approach is mainly based on the current fact that variant calling of indels, mid-sized deletion and duplications from NGS data is still often more robust from multi-gene-panels. Moreover, complete coverage of all genes and all coding regions might not be achieved for 100% of the coding regions by WES. However, we also note that WES technology as well as its bioinformatics applications for the detection of structural changes are steadily improving. Applying whole genome sequencing in routine diagnostics in the future certainly will change this strategy allowing high quality sequencing and analysis of all genes.

The results of the MRI will decisively guide the subsequent genetic testing. E.g., neuroimaging features of PTBHS are pathognomonic, and if this pattern is seen on MRI, LAMA1 analysis can be initiated straightforwardly. Detection of a brain malformation like lissencephaly or consistent with a tubulinopathy will prompt appropriate NGS panel testing, and a JBTS panel would be misleading in these cases.

As discussed above, the numerous subtypes of JBTS account for the vast majority of cases of COMA. Results of the abovementioned examinations might allow for narrowing down the spectrum of genetic conditions associated with COMA in general and thus may help in piloting the evaluation of the molecular genetic findings in a given patient. If molecular genetic testing reveals a JBTS subtype known to be associated with nephronophthisis, investigation of renal function (glomerular filtration rate, urine osmolality value [24]) and renal ultrasound are recommended.

In subjects with inconclusive neuroimaging, laboratory investigations accounting for various very rare causes of COMA (e.g. A-T, Gaucher disease, succinic semialdehyde dehydrogenase deficiency, to name just a few) are advisable. Depending on the local availability, early implementation of WES may shorten the duration of the diagnostic trajectory.

留言 (0)

沒有登入
gif