Motor Apraxia Research Articles

Évaluation des dysarthries et des apraxies de la parole : quelles approches ?

Context. In clinical practice, acquired motor speech disorders (MSDs), dysarthria and/or apraxia of speech (AoS) are mainly assessed using a perceptual approach. This approach remains dominant despite the biases associated with phonemic restoration and the subjectivity of the listener's internal representations. Furthermore, there is a lack of international consensus on the main diagnostic criteria for AoS. Several of these features are shared with dysarthria, which also often coexists with AoS (Duffy, 2019). In this context, the assessment of MSDs for differential diagnosis is a major challenge. Aims. This article provides an overview of the studies resulting from our PhD thesis. The aim of the thesis was to examine the contribution of the perceptual, acoustic and cognitive approaches to the assessment of dysarthria and AoS for the diagnosis and characterisation of these MSDs. Methods. Three studies were conducted on 4 groups of speakers: neurotypical, pathological speakers with AoS, hypokinetic dysarthria in Parkinson's disease, and mixed flaccid-spastic dysarthria in amyotrophic lateral sclerosis. These studies, partly based on the MonPaGe-2.0.s corpus (Fougeron et al., 2018 ; Laganaro et al., 2021 ; Pernon et al., 2020), focused on each of the following assessment approaches: (i) a multi-judge auditory-perceptual classification task of MSDs, (ii) a discrete phonetic-acoustic analysis by speech dimension of the speakers with the lowest and highest accuracy rates in (i), (iii) a dual-task paradigm evaluating the effects of attentional and executive demands on speech and non-verbal tasks in neurotypical speakers. Results. There was little difference between the perceptual and acoustic assessment approaches in diagnosing MSDs. The perceptual approach failed to diagnose very mild MSDs. The acoustic approach provided a quantified characterisation of MSDs profiles on average across three speech dimensions assessed by the MonPaGe-2.0.s tool, as in the study of perceptual classification of MSDs. The bidirectional dual-task effects showed that the mode of presentation of the stimuli and their modality, the type of speech task and the attentional demand of the non-verbal tasks had to be taken into account when developing and interpreting dual-task performance. These three studies found differences depending on the speech task. Conclusion. In addition to considering the speech dimensions involved in speech tasks, a more precise examination of their cognitive-motor demands on speech (type of speech task, phonetic and linguistic complexity of the corpus, speech production condition) refines the differential diagnosis of MSDs and improves their characterisation during assessment.

Case report on interesting cases of congenital ocular motor apraxia

Congenital ocular motor apraxia (COMA) is an uncommon disorder of ocular motility characterized by inability to initiate voluntary horizontal saccades with associated head thrusts during horizontal fixation shifts. In addition, when ocular movements typical of COMA are observed, detailed systemic and neurologic examination should be performed to rule out any associated congenital neurologic or metabolic disorder. We report two cases of COMA, a 14-year-old male with diminution of vision, esotropia, and his face turned to the right without any systemic disease, and a 9-year-old male with esotropia, no face turn, acute lymphocytic leukemia, and isolated complete agenesis of the corpus callosum. Both cases had abnormal saccadic initiation for horizontal gaze with head thrusts to take fixation. Both cases underwent Medial rectus (MR) recession, which improved face turn and strabismus, respectively.

Developmental, Cognitive, Ocular Motor, and Neuroimaging Findings Related to SUFU Haploinsufficiency: Unraveling Subtle and Highly Variable Phenotypes

Biallelic SUFU variants have originally been linked to Joubert syndrome, comprising cerebellar abnormalities, dysmorphism, and polydactyly. In contrast, heterozygous truncating variants have recently been associated with developmental delay and ocular motor apraxia, but only a limited number of patients have been reported. Here, we aim to delineate further the mild end of the phenotypic spectrum related to SUFU haploinsufficiency. Nine individuals (from three unrelated families) harboring truncating SUFU variants were investigated, including two previously reported individuals (from one family). We provide results from a comprehensive assessment comprising neuroimaging, neuropsychology, video-oculography, and genetic testing. We identified three inherited or de novo truncating variants in SUFU (NM_016169.4): c.895C>T p.(Arg299∗), c.71dup p.(Ala25Glyfs∗23), and c.71del p.(Pro24Argfs∗72). The phenotypic expression showed high variability both between and within families. Clinical features include motor developmental delay (seven of nine), axial hypotonia (five of nine), ocular motor apraxia (three of nine), and cerebellar signs (three of nine). Four of the six reported children had macrocephaly. Neuropsychological and developmental assessments revealed mildly delayed language development in the youngest children, whereas general cognition was normal in all variant carriers. Subtle but characteristic SUFU-related neuroimaging abnormalities (including superior cerebellar dysplasia, abnormalities of the superior cerebellar peduncles, rostrally displaced fastigium, and vermis hypoplasia) were observed in seven of nine individuals. Our data shed further light on the mild but recognizable features of SUFU haploinsufficiency and underline its marked phenotypic variability, even within families. Notably, neurodevelopmental and behavioral abnormalities are mild compared with Joubert syndrome and seem to be well compensated over time.

Isolated pure motor apraxia in the setting of depressed skull fracture: A case report and review of the literature

Introduction: An isolated pure apraxia of speech following head trauma is a rare clinical presentation in the absence of any other neurologic deficit. It is more commonly seen in patients with vascular pathology. Confusion can exist in recognizing an apraxia of speech versus a true Broca’s aphasia. We report such a case in a patient undergoing significant head trauma. The pathology and its management are discussed. Case Report: A 41-year-old male presented to our Emergency Department with a 3 cm laceration to the left side of the head following an assault with an unknown object. The patient suffered a depressed skull fracture with underlying epidural hematoma, bilateral traumatic subarachnoid hemorrhages, and a resultant isolated pure motor apraxia of speech. He was treated effectively with an emergency frontoparietal craniotomy, elevation and repair of his skull fracture, and evacuation of his epidural hematoma. His pure motor apraxia was greatly improved post-operatively and the patient was referred to outpatient speech therapy with continued neurosurgical follow-up. Conclusion: This case represents the unusual presentation of a pure motor apraxia of speech following traumatic assault to the left frontoparietal skull. An excellent therapeutic response was obtained following surgical intervention and speech therapy.

Intraoperative stimulation mapping of thalamocortical tracts in asleep and awake settings: novel electrophysiological, anatomical, and tractographic paradigms.

Despite the disabling deficits of motor apraxia and sensory ataxia resulting from intraoperative injury of the superior thalamocortical tracts (TCTs), region-specific electrophysiological localization is currently lacking. Herein, the authors describe a novel TCT mapping paradigm. Three patients, 1 asleep and 2 awake, underwent glioma resection affecting primarily the somatosensory cortex and underlying TCT. Stimulation was performed at the median, ulnar, and posterior tibial nerves. Parameters comprised single anodal pulses (duration 200-500 μsec, 2.1-4.7 Hz) with a current ranging from 10 to 25 mA. Recordings were captured with a bipolar stimulation probe, avoiding the classic collision technique. Positive localization sites were used to tractographically reconstruct the TCT in the third case. Employing one electrophysiological paradigm, the TCT was localized subcortically in all 3 cases by using a bipolar probe, peak range of 19.6-29.2 msec, trough of 23.3-34.8 msec, stimulation range of 10-25 mA. In the last case, tractographic reconstruction of the TCT validated a highly accurate TCT localization within a specific region of the posterior limb of the internal capsule. The authors describe the first electrophysiological technique for intraoperative localization and protection of the TCT in both asleep and awake craniotomies with tractographic validation, while avoiding the collision paradigm. None of the above paradigms have been previously reported. More data are required to further validate this technique.

Visual Development in a Patient with Infantile-Onset Saccade Initiation Delay

Congenital ocular motor apraxia (COMA), also known as infantile-onset saccade initiation delay (ISID), is characterized by the inability to initiate volitional horizontal saccades. This five-month-old girl showed constant rapid movements to right or left one week after birth. After four months, she began thrusting her head from left to right when following target objects. She was diagnosed with COMA/ISID. At 4 years of age, head thrust became less evident. She first uttered meaningful words at 5 years of age, and spoke in sentences by 6 years of age. At 6 years of age, visual acuity was 1.0 in both eyes at 1 m. Head thrust disappeared at almost 6 years of age. She could not start crawling and sustaining a sitting position due to hypotonia. Clinicians should be aware of visual development in COMA/ISID and should look for them during the assessment of these children.

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

BackgroundThe term congenital ocular motor apraxia (COMA), coined by Cogan in 1952, designates the incapacity to initiate voluntary eye movements performing rapid gaze shift, so called saccades. While regarded as a nosological entity by some authors, there is growing evidence that COMA designates merely a neurological symptom with etiologic heterogeneity. In 2016, we reported an observational study in a cohort of 21 patients diagnosed as having COMA. Thorough re-evaluation of the neuroimaging features of these 21 subjects revealed a previously not recognized molar tooth sign (MTS) in 11 of them, thus leading to a diagnostic reassignment as Joubert syndrome (JBTS). Specific MRI features in two further individuals indicated a Poretti–Boltshauser syndrome (PTBHS) and a tubulinopathy. In eight patients, a more precise diagnosis was not achieved. We pursued this cohort aiming at clarification of the definite genetic basis of COMA in each patient.ResultsUsing a candidate gene approach, molecular genetic panels or exome sequencing, we detected causative molecular genetic variants in 17 of 21 patients with COMA. In nine of those 11 subjects diagnosed with JBTS due to newly recognized MTS on neuroimaging, we found pathogenic mutations in five different genes known to be associated with JBTS, including KIAA0586, NPHP1, CC2D2A, MKS1, and TMEM67. In two individuals without MTS on MRI, pathogenic variants were detected in NPHP1 and KIAA0586, arriving at a diagnosis of JBTS type 4 and 23, respectively. Three patients carried heterozygous truncating variants in SUFU, representing the first description of a newly identified forme fruste of JBTS. The clinical diagnoses of PTBHS and tubulinopathy were confirmed by detection of causative variants in LAMA1 and TUBA1A, respectively. In one patient with normal MRI, biallelic pathogenic variants in ATM indicated variant ataxia telangiectasia. Exome sequencing failed to reveal causative genetic variants in the remaining four subjects, two of them with clear MTS on MRI.ConclusionsOur findings indicate marked etiologic heterogeneity in COMA with detection of causative mutations in 81% (17/21) in our cohort and nine different genes being affected, mostly genes associated with JBTS. We provide a diagnostic algorithm for COMA.

Cerebral Visual Loss.

Cerebral visual disorders include a range of common and rare deficits. They can be divided into effects on low-, intermediate-, and high-level forms of visual processing. Low-level deficits are various forms of homonymous hemifield scotomata, which affect all types of vision within their borders. Intermediate-level deficits refer to impairments of colour or motion perception, which affect either one hemifield or the entire field when lesions are bilateral. High-level deficits are divided into those of the ventral (occipitotemporal) or dorsal (occipitoparietal) stream. Occipitotemporal lesions affect various aspects of object recognition, ranging from general visual agnosia to selective agnosias, such as prosopagnosia or topographagnosia from right or bilateral lesions, and pure alexia from left-sided lesions. Occipitoparietal lesions cause the various components of Bálint syndrome, namely, simultanagnosia, optic ataxia, and ocular motor apraxia. They can also cause other impairments of visuospatial or visuotemporal processing, such as astereopsis and sequence-agnosia. Because of anatomic proximity, certain deficits cluster together to form a number of cerebral visual syndromes. Treatment of these disorders remains challenging, with frequent reliance on strategic substitutions rather than restorative approaches.

Suspicious ultrasound markers of joubert syndrome can lead to early prenatal diagnosis

Joubert syndrome is a rare autosomal recessive inherited disease associated with many signs and symptoms. Joubert syndrome (JS) was first discovered by Marie Joubert in 1969. Joubert’s syndrome presents as low muscle tone (hypotonia), have difficulty coordinating movements (ataxia), have episodes of fast or slow breathing and abnormal eye movement (ocular motor apraxia). Developmental delay and intellectual disability generally accompany. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen. The main aim should be to diagnose these cases antenatally. Number of ultrasound features have been described which are indicator of possibility of Joubert’s syndrome. The confirmatory diagnosis then can be done by MRI. We describe a case of suspicious JS prenatally who had previous baby diagnosed as JS after termination at 20 weeks. We also discuss the antenatal diagnostic management of pregnancies who have a previous history or at high risk of Joubert’s syndrome.

De novo heterozygous variants in SLC30A7 are a candidate cause for Joubert syndrome.

Joubert syndrome (JS), a well-established ciliopathy, is characterized by the distinctive molar tooth sign on brain MRI, ataxia, and neurodevelopmental features. Other manifestations can include polydactyly, accessory frenula, renal, or liver disease. Here, we report individuals meeting criteria for JS with de novo heterozygous variants in SLC30A7 (Chr1p21.2). The first individual is a female with history of unilateral postaxial polydactyly, classic molar tooth sign on MRI, macrocephaly, ataxia, ocular motor apraxia, neurodevelopmental delay, and precocious puberty. Exome sequencing detected a de novo heterozygous missense variant in SLC30A7: NM_133496.5: c.407 T > C, (p.Val136Ala). The second individual had bilateral postaxial polydactyly, molar tooth sign, macrocephaly, developmental delay, and an extra oral frenulum. A de novo deletion-insertion variant in SLC30A7, c.490_491delinsAG (p.His164Ser) was found. Both de novo variants affect highly conserved residues. Variants were not identified in known Joubert genes for either case. SLC30A7 has not yet been associated with a human phenotype. The SLC30 family of zinc transporters, like SLC30A7, permit cellular efflux of zinc, and although it is expressed in the brain its functions remain unknown. Published data from proteomic studies support SLC30A7 interaction with TCTN3, another protein associated with JS. The potential involvement of such genes in primary cilia suggest a role in Sonic Hedgehog signaling. SLC30A7 is a candidate JS-associated gene. Future work could be directed toward further characterization of SLC30A7 variants and understanding its function.

Variable Phenotypes of ZC4H2-Associated Rare Disease in Six Patients

PurposeWieacker-Wolff syndrome is a rare disease caused by X-linked zinc finger C4H2-type containing (ZC4H2) mutations. It is characterized by arthrogryposis multiplex congenita (AMC) and intellectual disability (ID), including impairment of central and peripheral synaptic plasticity. Currently, it is named “ZC4H2-associated rare disease” (ZARD) due to various clinical features other than AMC and ID. Here, we report six cases of ZARD, and describe their variable clinical phenotypes.MethodsWe analyzed the detailed clinical features and genotypes of six patients diagnosed by whole-exome sequencing or a chromosomal microarray.ResultsIn the four male patients, hemizygous mutations were found (c. 245A>C in two patients, c. 610C>A in one patient, and c.637C>T in one patient), and all variants were identified by Sanger sequencing. In the female patients, a 1.16-Mb deletion in Xq11.2, including ZC4H2, was identified by chromosomal microarray. All patients had heterogeneous phenotypes with variable severities. Motor delay was observed in all patients, four of whom could not walk independently. Other neurological features included ID, spasticity, and seizures. The craniofacial features included microcephaly, low-set ears, strabismus, ptosis, ocular motor apraxia, a U-shaped upper lip vermilion, short neck, and microretrognathia. The most common musculoskeletal symptoms were multiple arthrogryposis: metacarpophalangeal joint contracture, clubfoot, distal muscle weakness, Achilles tendon contracture, knee flexion contracture, camptodactyly, elbow flexion contracture, and hip subluxation.ConclusionThe ZARD phenotypes were prominent in male patients, and female patients with loss of function showed more severe symptoms. Further research is needed to clarify phenotypic variability in this rare disorder.

EP230: The effects of early androgen therapy on behavior in boys with 47,XXY under 6 years old

47,XXY, Klinefelter syndrome, is the most common sex chromosome aneuploidy (SCA), typically occurring in 1 in 650 male births worldwide. This disorder is characterized by decreased testicular size, tall stature, with eunuchoid body type, and low fertility. It is often associated with language-based learning difficulties, motor apraxia, speech and language delays, and neuromotor dysfunction.

Characteristics and Outcomes of Idiopathic and Non-idiopathic Ocular Motor Apraxia in Children.

To systematically compare idiopathic and non-idiopathic ocular motor apraxia (OMA) in children. A retrospective chart review was conducted of all children (< 18 years) diagnosed as having OMA from 2010 to 2020. Demographics, clinical characteristics, and oculomotor outcomes were compared for children with idiopathic and non-idiopathic OMA. Thirty-seven children were included, 17 (46%) with idiopathic OMA and 20 (54%) with non-idiopathic OMA. Among patients with non-idiopathic OMA, Joubert syndrome was the most frequent underlying diagnosis (30%). Strabismus (45% vs 12%, P = .04), nystagmus (30% vs 0%, P = .02), and vertical saccade involvement (25% vs 0%, P = .049) were significantly more common in non-idiopathic than idiopathic OMA, respectively. Neuroimaging abnormalities (90% vs 18%, P < .0001) and developmental delays (100% vs 59%, P = .002) were also more frequent in non-idiopathic than idiopathic OMA, respectively. Endocrine disorders (most commonly growth hormone deficiency) were diagnosed in 12% and 20% of children with idiopathic and non-idiopathic OMA, respectively (P = .67). On survival curve analysis, improvement in OMA occurred faster and more frequently in children with idiopathic than non-idiopathic OMA (median time to improvement 56 vs 139 months, respectively, P = .034). Non-idiopathic OMA is associated with a higher rate of vertical saccade involvement, nystagmus, and developmental delays. These findings should prompt neuroimaging in children with OMA. Additionally, endocrine disorders may be more frequent in children with OMA than the general pediatric population. [J Pediatr Ophthalmol Strabismus. 2022;59(5):326-331.].

A Novel SETX Mutation in a Taiwanese Patient with Autosomal Recessive Cerebellar Ataxia Detected by Targeted Next-Generation Sequencing, and a Literature Review.

Ataxia with oculomotor apraxia type 2 (AOA2), also known as autosomal recessive spinocerebellar ataxia with axonal neuropathy-2 (SCAN2) (OMIM #606002), is a neurodegenerative disorder characterized by early-onset progressive cerebellar ataxia, polyneuropathy, and elevated levels of alpha-fetoprotein. It is caused by mutations in the SETX (OMIM #608465) gene. The prevalence of this disease is widely varied, from non-existent up to 1/150,000, depending on the region. Until now, no cases of AOA2/SCAN2 have been reported in Taiwan. Methods: Next-generation sequencing was used to detect disease-causing mutations of SETX in a Taiwanese patient presenting with autosomal recessive cerebellar ataxia, polyneuropathy, and elevated alpha-fetoprotein. The candidate mutations were further confirmed by polymerase chain reaction (PCR) and Sanger sequencing. Results: A compound heterozygous mutation of SETX c.6859C > T (p.R2287X) and c.7034-7036del was identified. The c.6859C > T (p.R2287X) has been previously found in a Saudi Arabia family, whereas c.7034-7036del is a novel mutation. Both mutations were predicted by bioinformatics programs to be likely pathogenic (having a damaging effect). We also reviewed the literature to address the reported clinical features of AOA2 from different populations. Conclusions: To our knowledge, we are the first to report a Taiwanese patient with AOA2/SCAN2, a result obtained by utilizing next-generation sequencing. The literature review shows that ataxia, polyneuropathy, and elevated AFP are common features and ocular motor apraxia (OMA) is a variable sign of AOA2 from different populations. OMA is rare and saccadic ocular pursuit and nystagmus are common in East Asian AOA2.

Delayed Diagnosis of Childhood-Onset Huntington Disease in an 8-Year-Old Boy With Ocular Motor Apraxia.

Delayed Diagnosis of Childhood-Onset Huntington Disease in an 8-Year-Old Boy With Ocular Motor Apraxia.

Get Your Molar Tooth Right: Joubert Syndrome Misdiagnosis Unmasked by Whole-Exome Sequencing

Joubert syndrome (JS) is a recessively inherited ciliopathy, characterized by a specific cerebellar and brainstem malformation recognizable on brain imaging as the "molar tooth sign" (MTS). Clinical signs include hypotonia, developmental delay, breathing abnormalities, and ocular motor apraxia. Older patients develop ataxia, intellectual impairment, and variable organ involvement. JS is genetically heterogeneous, with over 40 ciliary genes overall accounting for 65-75% cases. Thus, in recent years, the genetic diagnosis of JS has been based on the analysis of next-generation sequencing targeted gene panels. Since clinical features are unspecific and undistinguishable from other neurodevelopmental syndromes, the recognition of the MTS is crucial to address the patient to the appropriate genetic testing. However, the MTS is not always properly diagnosed, resulting either in false negative diagnoses (patients with the MTS not addressed to JS genetic testing) or in false positive diagnoses (patients with a different brain malformation wrongly addressed to JS genetic testing). Here, we present six cases referred for JS genetic testing based on inappropriate recognition of MTS. While the analysis of JS-related genes was negative, whole-exome sequencing (WES) disclosed pathogenic variants in other genes causative of distinct brain malformative conditions with partial clinical and neuroradiological overlap with JS. Reassessment of brain MRIs from five patients by a panel of expert pediatric neuroradiologists blinded to the genetic diagnosis excluded the MTS in all cases but one, which raised conflicting interpretations. This study highlights that the diagnostic yield of NGS-based targeted panels is strictly related to the accuracy of the diagnostic referral based on clinical and imaging assessment and that WES has an advantage over targeted panel analysis when the diagnostic suspicion is not straightforward.

SUFU haploinsufficiency causes a recognisable neurodevelopmental phenotype at the mild end of the Joubert syndrome spectrum

BackgroundJoubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation....

Immunological abnormalities in patients with early-onset ataxia with ocular motor apraxia and hypoalbuminemia

Early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH) is a neurodegenerative disorder caused by mutation in the aprataxin (APTX)-coding gene APTX, which is involved in DNA single-strand break repair (SSBR). The neurological abnormalities associated with EAOH are similar to those observed in patients with ataxia-telangiectasia. However, the immunological abnormalities in patients with EAOH have not been described. In this study, we report that EAOH patients have immunological abnormalities, including lymphopenia; decreased levels of CD4+ T-cells, CD8+ T-cells, and B-cells; hypogammaglobulinemia; low T-cell recombination excision circles and kappa-deleting element recombination circles; and oligoclonality of T-cell receptor β-chain variable repertoire. These immunological abnormalities vary among the EAOH patients. Additionally, mild radiosensitivity in the lymphocytes obtained from the patients with EAOH was demonstrated. These findings suggested that the immunological abnormalities and mild radiosensitivity evident in patients with EAOH could be probably caused by the DNA repair defects.

Maternal transmission of a mild Coffin\u2013Siris syndrome phenotype caused by a SOX11 missense variant

Here we report for the first time on the maternal transmission of mild Coffin–Siris syndrome (CSS) caused by a SOX11 missense variant. We present two sisters with intellectual disability and muscular hypotonia born to non-consanguineous parents. Cogan ocular motor apraxia was present in both sisters. Body measurements were in a normal range. The mother and both daughters showed hypoplastic nails of the fifth toes. A missense variant in SOX11 [c.139 G > A; p.(Gly47Ser)] in both sisters and their mother was identified. Since 2014, variants in SOX11 are known to cause mild CSS. Most described patients showed intellectual disability, especially concerning acquired language. All of them had hypoplastic nails of the fifth toes. It is of note, that some of these patients show Cogan ocular motor apraxia. The facial dysmorphic features seem not to be specific. We suggest that the combination of Cogan ocular motor apraxia, hypoplastic nails of fifth toes, and developmental delay give the important diagnostic clue for a variant in the SOX11 gene (OMIM 615866, MR 27).

Heterozygous truncating variants in SUFU cause congenital ocular motor apraxia

PurposeThis study aimed to delineate the genetic basis of congenital ocular motor apraxia (COMA) in patients not otherwise classifiable.MethodsWe compiled clinical and neuroimaging data of individuals from six unrelated families with distinct clinical features of COMA who do not share common diagnostic characteristics of Joubert syndrome or other known genetic conditions associated with COMA. We used exome sequencing to identify pathogenic variants and functional studies in patient-derived fibroblasts.ResultsIn 15 individuals, we detected familial as well as de novo heterozygous truncating causative variants in the Suppressor of Fused (SUFU) gene, a negative regulator of the Hedgehog (HH) signaling pathway. Functional studies showed no differences in cilia occurrence, morphology, or localization of ciliary proteins, such as smoothened. However, analysis of expression of HH signaling target genes detected a significant increase in the general signaling activity in COMA patient–derived fibroblasts compared with control cells. We observed higher basal HH signaling activity resulting in increased basal expression levels of GLI1, GLI2, GLI3, and Patched1. Neuroimaging revealed subtle cerebellar changes, but no full-blown molar tooth sign.ConclusionTaken together, our data imply that the clinical phenotype associated with heterozygous truncating germline variants in SUFU is a forme fruste of Joubert syndrome.