Clinical Signs

In humans with mitochondrial encephalopathy, severity can vary from acute life-threatening disease to a subacute progressive degenerative disorder. Progression may be unrelenting with rapid deterioration over hours, episodic with intermittent decompensations and asymptomatic intervals, or insidious with slow degeneration over decades. The presenting clinical signs of these neurometabolic diseases often are very non specific and are caused by progressive destruction of motor, mental, and perceptual functions potentially associated with seizures and with earlier death, often before adulthood.

As in people, relatively nonspecific, progressive or episodic, classically life-threatening signs of CNS dysfunction related to neurometabolic diseases have been reported in isolated cases or families of dogs (Table 228-1). Since the neurons have the highest metabolic demand of the different brain cells, the cerebral cortex is the most susceptible to energy metabolism disorders. Thus the overwhelming majority of animals with metabolic encephalopathies initially experience neurologic signs referable to forebrain dysfunction; these signs then can progress to more generalized brain involvement (brainstem or cerebellar signs may develop later on) and eventually death. The neurologic signs usually develop in the first year of life; however, the age of onset may vary from as young as 4 months to 6 years or older. Clinical signs usually are compatible with a generalized bilateral and symmetric encephalopathy or a multifocal CNS disease (e.g., cerebrum and cerebellum, or cerebrum and spinal cord).

Clinical signs generally correlate well with the location of structural lesions observed on gross and microscopic examination of the CNS. However, the abnormalities also may reflect a functional disturbance of neuronal populations not visible by light microscopy, and this is relatively common in metabolic disorders. In cases of forebrain localization, mental obtundation, blindness, and behavioral changes with or without seizures have been reported most commonly. Brainstem-cerebellar signs such as generalized ataxia, dysmetria, and a wide-based stance also have been reported with a relatively high frequency. A combination of these signs is seen with a diffuse or multifocal problem.

Encephalopathies proved or suspected to be due to a mitochondrial disorder have been reported sporadically in Alaskan huskies, Yorkshire terriers, Jack Russell terriers, springer spaniels, Shih Tzus, Australian cattle dogs, and Shetland sheepdogs. However, other dogs previously reported to have vacuolar or spongiform encephalopathy of idiopathic origin currently are suspected to have an underlying mitochondrial dysfunction. The encephalopathy described in the Alaskan husky shares many similarities with that reported in the Yorkshire terrier, springer spaniel, and, to a lesser degree, the Jack Russell terrier and resembles subacute necrotizing encephalomyelopathy, or Leigh’s syndrome, in humans. This syndrome includes a heterogeneous group of heritable neurodegenerative diseases. Currently, most of the diseases reported are known to be caused by diverse defects of the mitochondrial respiratory chain.

In dogs with changes similar to those in Leigh’s syndrome, the clinical signs usually include ataxia (mostly cerebellar-quality ataxia), seizures, behavioral abnormalities (including obtundation and propulsive pacing), and visual deficits. Moreover, the neurologic examination commonly reveals delayed postural reactions and some other cerebellovestibular signs like nystagmus and head tremor. Varying degrees of tetraparesis, facial hypalgesia, and difficulty in prehending food also have been reported in Alaskan huskies.

In Australian cattle dogs, after an initial presentation of psychomotor seizures (episodes of running in circles, vocalizing, and urinating), usually progressive fatigue and thoracic limb stiffness, and eventually spastic tetraparesis occur over a 6- to 12-month period (Harkin et al, 1999; Brenner et al, 1997b). In one dog, the thoracic limb stiffness was exacerbated while the dog was placed in lateral recumbency; the thoracic limbs were in fact rigidly extended in a tetanic posture with persistent contraction of extensor muscles (Harkin et al, 1999). In the single Shih Tzu recently reported in which a mitochondrial CNS disease was suspected, the signs initially were compatible with a progressive bilateral brachial plexus–caudal cervical spinal cord disorder that mostly spared the back legs; only later did the dog develop concurrent brain signs consisting of behavioral changes such as aggressiveness and vocalization (Kent et al, 2009). In the Shetland sheepdogs the clinical signs were intermittent, present from puppyhood, and composed mainly of seizures. As the disease progressed, depressed mental status, hypermetric gait, and intention head and neck tremor developed, and ultimately these dogs became unable to walk, with extensor spasticity of all four limbs (Wood et al, 2001).