Oculodentodigital Dysplasia Presenting as Spastic Paraparesis: The First Genetically Confirmed Korean Case and a Literature Review.

Oculodentodigital dysplasia (ODDD) is a rare autosomal dominant inherited disease caused by mutations of the human gap junction alpha 1 gene, which encodes the protein Connexin-43. Patients with ODDD may present with neurological deficits with a typical pleiotropic combination of characteristic craniofacial, ophthalmological, phalangeal, and dental anomalies. In this report, we describe the first genetically confirmed Korean ODDD patient, who presented with spastic paraparesis. We will also review the neurological aspects of ODDD as reported in the literature.

Oculodentodigital dysplasia (ODDD, OMIM #164200) is a rare autosomal dominant inherited disorder. ODDD is caused by the mutation of the human gap junction alpha 1 (GJA1) gene, which encodes the protein, Connexin-43 (Cx43) [1]. ODDD patients present with heterogeneous phenotypic combinations of craniofacial, ophthalmological, phalangeal, dental, and neurological symptoms [1-4]. Neurological manifestations have been reported to be present in approximately 30% of ODDD patients [4]. In this report, we describe the first genetically confirmed Korean ODDD patient, who presented with spastic gait disturbance.

CASE REPORT

A 40-year-old female visited our neurology clinic because of gait disturbance. She was born to term with syndactyly of her bilateral fourth and fifth finger (syndactyly type III), which was surgically corrected. There was no developmental delay, but she was always in last place in her class in track and field. She had been working as a salesperson since graduating from high school. She began to feel stiffness in her legs in her mid-30s. She also suffered from urinary frequency and incomplete voiding of urine. These symptoms worsened over the following five years. Her father had suffered intracerebral hemorrhage 2 years prior but did not manifest with any gait problems. She was married and had two children, but none of her siblings, children, or nephews had a gait problem (Figure 1A). There was no history of seizures.

Figure 1.

Family pedigree (A). Black arrow indicates the proband. Complementary sequence of the patient’s GJA1 gene is transited from C to T, indicating c.61G > A (p.G21R) mutation of the template strand (B). Craniofacial appearance of the case and her hands are shown in (C). Microphthalmia, thin nose, hypoplastic alae nasi, epicanthic folds, and clinodactyly of the bilateral fourth finger are shown. Magnetic resonance imaging of the patient (D). Aberrant T2 high signal intensities of white matter extends to the brainstem and spinal cord. GJA1: gap junction alpha 1.

Upon physical examination, she was found to have microphthalmia with small sunken eyes, thin nose, hypoplastic ale nasi, and bilateral epicanthic folds. In her hands, there were scars from previous surgeries for syndactyly type III and campylodactyly (fixed flexion of deformity of the fingers and toes) of bilateral fourth fingers (Figure 1C). Her skin and hair were brittle and dry.

Upon neurological examination, there was spasticity, generalized hyperreflexia, Babinski’s sign, and ankle clonus on her lower extremities. She also showed bilateral Hoffman’s sign. Scissor gait was observed. Her mini-mental status examination score was 30 out of 30. On brain MRI, there were diffuse high signal intensities of bilateral cerebral white matter from the juxta-cortical area to the deep white matter, extending to the brainstem. There was diffuse atrophy of the brain, brainstem and spinal cord (Figure 1D). She also complained of urinary frequency and nocturia. She had 200–300 cc of residual urine after urination and needed intermittent catheterization. Her visual and auditory functions were unremarkable. Nerve conduction studies of her bilateral median, ulnar, peroneal, and tibial nerves were also unremarkable. Transcranial magnetic motor-evoked potentials from her bilateral tibialis anterior muscles were normal after lumbar stimulation but were unobtainable after cortical stimulation, suggesting central conduction block in the corticospinal tract.

Sanger sequencing of the patient’s GJA1 gene using her peripheral blood samples identified the heterozygous missense mutation c.61G > A (Figure 1B), which had been previously reported as a pathogenic mutation [1,4]. No mutations were found in the SPG3A or SPG4 genes. Clonazepam, baclofen, and trihexyphenidyl were administered for symptomatic relief, which resulted in mild improvement of spasticity of her lower extremities.

DISCUSSION

This patient presented in our movement clinic with spastic gait disturbance. Although ODDD is not the first-line differential diagnosis for adult onset spastic paresis due to its extreme rarity, her distinct craniofacial and digital features led us to perform the diagnostic gene test. The case showed the typical features of ODDD, including craniofacial dysmorphisms, syndactyly, spastic gait disturbance, and abnormal high signal intensities in the bilateral cerebral white matter on brain MRI. To the best of our knowledge, she is the first genetically confirmed ODDD case in Korea. In previous reports, affected individuals have been mostly Caucasians [4]. Since the causative gene was identified in 2003, cases from East Asia have been accumulating, including our patient [5-7].

ODDD is caused by the mutation in the GJA1 gene that encodes the protein Cx43, which is a member of the gap junction family protein. In the central nervous system, Cx43 gap junction channels are mostly found in astrocytes [2]. Defective Cx43 proteins by the mutation in GJA1 gene results in non-functional gap junctions and aberrant signaling in astrocytes [2,8]. At present, according to the HGMD® Public database, 2017. 6, there are 89 different mutations that are associated with ODDD [9]. Among the reported mutations, more than 30 have been associated with neurological involvement. The mutations, neurological symptoms, origins, and obtained literature are summarized in Table 1.

Table 1.

GJA1 gene mutations associated with documented neurological phenotype of oculodentodigital dysplasia in the literature review

Protein change	Nucleotide change	Neurological symptoms	Origin	Age at diagnosis	Reference (years)
p.D3N	n.d.	UMN, NB, Uthoff's sign	n.d.	14	Churko et al. (2011)
p.L11F	c.31C > T	hyperactivity disorder, sensorineural hearing loss	Poland	3.5	Jamsheer et al. (2009)
p.Y17S	c.50A > C	UMN, NB	Canada	22‒61	Paznekas et al. (2009)
pS18P	c.52T > C	bilateral optic atrophy, MRI WMC	France	5	Alao et al. (2009)
p.G21R	c.61G > A	UMN	n.d.	6	Paznekas et al. (2009)
p.G22E	c.65G > A	UMN, MRI WMC, headache, Tremor	USA	14	Paznekas et al. (2009)
p.K23T	c.68A > C	UMN, MRI WMC, tremor, delayed speech	USA	12	Paznekas et al. (2009)
p.W25C	c.77G > T	UMN, MRI WMC	Japan	34	Furata et al. (2012)
p.W25C	c.75G > T	MRI WMC without neurological deficit	India	7	Dwarakanathan et al. (2015)
p.R33X	c.97C > T	UMN, MRI WMC	Pakistan	1‒3.5	Paznekas et al. (2009)
p.A40V	c.119C > T	gait difficulty, NB	n.d.	8‒48	Paznekas et al. (2009)
p.Q42G	c.124G > C	UMN, bipolar disorder, calcification of basal ganglia and dentate nucleus	Italy	59	Tumminelli et al. (2016)
p.Q49P	c.146A > C	NB	Austria/Turkey	9	Paznekas et al. (2009)
p.R76S	c.226C > A	MRI WMC, Sz	USA	0‒adult	Paznekas et al. (2009)
p.R76C	c.226C > T	Cerebral infarction due to cardiac anomaly	Japan	0	Izumi et al. (2013)
p.S86Y	c.257C > A	Mental retardation	Austria	0	Jamsheer et al. (2014)
p.L90V	c.268C > G	UMN, NB, Sz	Norway	7‒62	Paznekas et al. (2009)
p.H95R	c.284A > G	UMN, NB, MRI WMC	n.d.	Unknown‒47	Paznekas et al. (2009)
p.V96A	c.287T > C	MRI WMC	Australia	2	Paznekas et al. (2009)
p.K102N	c.306G > C	NB	n.d.	4‒27	Paznekas et al. (2009)
p.L106P	c.317T > C	UMN, NB	n.d.	60	Paznekas et al. (2009)
p.L113P	c.338T > C	UMN, MRI WMC	n.d.	35‒63	Paznekas et al. (2009)
p.I130T	c.389T > C	UMN, NB, Sz, MRI WMC & atrophy of spinal cord	USA	17‒71	Amador et al. (2008)
p.K134E	c.400A > G	UMN, MRI WMC	Russia	29	Paznekas et al. (2009)
p.K134N	c.402G > T	UMN	n.d.	Unknown	Paznekas et al. (2009)
p.G138R	c.412G > C	UMN, NB, MRI WMC	England/Ireland	11‒Adult	Paznekas et al. (2009)
p.G138S	c.412G > A	MRI WMC without neurological deficit	Japan	22	Kogame et al. (2014)
p.T154A	c.460A > G	UMN, NB, MRI WMC	n.d.	10	Paznekas et al. (2009)
p.T154N	c.461C > A	UMN, NB, tremor	n.d.	15‒47	Paznekas et al. (2009)
p.V216L	c.646G > T	UMN, NB, MRI WMC	Ireland	2‒41	Paznekas et al. (2009)
p.S220Y	c.659C > A	Developmental disorder	Germany	3	Wiest et al. (2006)
p.Y230CfsX6	c.689_690delTA	Mental retardation	France	22	Alao et al. (2009)
p.G2fsX7, p.R101X[*]	c.6delT(p.G2fsX7), c.301C > T(p.R101X)	Mental retardation, Sz, massive calcification of basal ganglia and dentate nucleus, hypomyelination, atrophy	Poland	15	Jamsheer et al. (2010)
n.d.	n.d.	UMN, Sz	Iran	11	Barzegar et al. (2012)
n.d.	n.d.	UMN, immature behavior, tremor, MRI WMC	Iran	22	Shakiba et al. (2012)

References are summarized in Supplementary Material.

compound heterozygous.

GJA1: gap junction alpha 1, n.d: not documented, UMN: upper motor neuron signs including spasticity, hyperreflexia, pathological reflexes, NB: neurogenic bladder or bowel signs, MRI WMC: magnetic resonance imaging white matter changes, Sz: seizure.

The prevalence of ODDD has been reported to be less than 1/1,000,000 [2]. This syndrome is highly penetrant with enormous intra- and interfamilial phenotypic variability [4]. The constellation of symptoms of ODDD is composed of typical craniofacial dysmorphisms, neurological manifestations, ophthalmological anomalies, dental anomalies, malformation of extremities, brittle hair/skin, and other miscellaneous features [3,4]. The craniofacial dysmorphisms (thin nose, hypoplastic alae nasi, small nares, and cleft lip and palate), malformation of the extremities (syndactyly, campylodactyly, and clinodactyly), dental features (microdontia and enamel hypoplasia), and ophthalmological anomalies (microphthalmia, microcornia, iris abnormalities, cataract, and glaucoma) are the most common, being observed in 92, 80, 70, and 68% of cases, respectively [1-4].

Neurological manifestations of ODDD include upper motor neuron signs including spasticity, neurogenic bladder, epilepsy, mental retardation, and abnormal brain imaging findings [3]. According to Paznekas et al. [4], neurological manifestations are seen in 30% of affected families. This number may have been underestimated for several reasons. First, neurological ODDD symptoms usually manifest later in life, typically in the third to fourth decades, whereas the craniofacial and digital findings are already evident at the time of birth. Second, neurological symptoms can be easily neglected if the diagnosis of ODDD is made by physicians with other specialties, especially when the symptoms are subtle. Moreover, there are cases that have not yet manifested neurological symptoms but have abnormal brain imaging findings [7,10]. Their neurological symptoms may become evident later in life. Thus, a thorough, multi-disciplinary, longitudinal approach for each patient is warranted.

The phenotypes of neurological manifestation may vary, as seen in Table 1. Meanwhile, in those who underwent brain imaging, they exhibited similar abnormal imaging findings, such as symmetrical generalized white matter signal changes extending to the brainstem, atrophy of the brainstem and cerebellum, and calcification of the basal ganglia and dentate nucleus [4,7,10]. This finding may reflect the degeneration of the corticospinal tract and related regions caused by the aberrant signaling of gap junctions of astrocytes.

In this report, we describe a new Korean ODDD case who presented spastic paraparesis. ODDD is rare and associated with variable multi-systemic manifestations. Thus, ODDD poses a considerable diagnostic challenge. Appropriate brain imaging, as well as detailed neurological examination, is necessary for each patient to evaluate the extent of neurological involvement.